Compositions useful as inhibitors of JAK and other protein kinases

ABSTRACT

The present invention provides a compound of formula I:  
                 
 
     or a pharmaceutically acceptable salt thereof. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of utilizing those compounds and compositions in the treatment of various protein kinase mediated disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority under 35 U.S.C. § 119 (e)to U.S. Provisional Application No. 60/422,973, filed Nov. 1, 2002,entitled “Compositions Useful as Inhibitors of Jak and Other ProteinKinases, the entire contents of which is hereby incorporated byreference.

TECHNICAL FIELD OF INVENTION

[0002] The present invention relates to compounds useful as inhibitorsof protein kinases. The invention also provides pharmaceuticallyacceptable compositions comprising the compounds of the invention andmethods of using the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

[0003] The search for new therapeutic agents has been greatly aided inrecent years by a better understanding of the structure of enzymes andother biomolecules associated with diseases. One important class ofenzymes that has been the subject of extensive study is protein kinases.

[0004] Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. (See, Hardie, G. and Hanks, S.The Protein Kinase Facts Book, I and II, Academic Press, San Diego,Calif.: 1995). Protein kinases are thought to have evolved from a commonancestral gene due to the conservation of their structure and catalyticfunction. Almost all kinases contain a similar 250-300 amino acidcatalytic domain. The kinases may be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, lipids, etc.). Sequence motifs have beenidentified that generally correspond to each of these kinase families(See, for example, Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576-596;Knighton et al., Science 1991, 253, 407-414; Hiles et al., Cell 1992,70, 419-429; Kunz et al., Cell 1993, 73, 585-596; Garcia-Bustos et al.,EMBO J. 1994, 13, 2352-2361).

[0005] Many diseases are associated with abnormal cellular responsestriggered by protein kinase-mediated events. These diseases includeautoimmune diseases, inflammatory diseases, bone diseases, metabolicdiseases, neurological and neurodegenerative diseases, cancer,cardiovascular diseases, allergies and asthma, Alzheimer's disease andhormone-related diseases. Accordingly, there has been a substantialeffort in medicinal chemistry to find protein kinase inhibitors that areeffective as therapeutic agents.

[0006] The Janus kinases (JAK) are a family of tyrosine kinasesconsisting of JAK1, JAK2, JAK3 and TYK2. The JAKs play a critical rolein cytokine signaling. The down-stream substrates of the JAK family ofkinases include the signal transducer and activator of transcription(STAT) proteins. JAK/STAT signaling has been implicated in the mediationof many abnormal immune responses such as allergies, asthma, autoimmunediseases such as transplant rejection, rheumatoid arthritis, amyotrophiclateral sclerosis and multiple sclerosis as well as in solid andhematologic malignancies such as leukemias and lymphomas. Thepharmaceutical intervention in the JAK/STAT pathway has been reviewed[Frank Mol. Med. 5, 432-456 (1999) & Seidel, et al, Oncogene 19,2645-2656 (2000)].

[0007] JAK1, JAK2, and TYK2 are ubiquitously expressed, while JAK3 ispredominantly expressed in hematopoietic cells. JAK3 binds exclusivelyto the common cytokine receptor gamma chain (Γ_(c)) and is activated byIL-2, IL-4, IL-7, IL-9, and IL-15. The proliferation and survival ofmurine mast cells induced by IL-4 and IL-9 have, in fact, been shown tobe dependent on JAK3- and Γ_(c)-signaling [Suzuki et al, Blood 96,2172-2180 (2000)].

[0008] Cross-linking of the high-affinity immunoglobulin (Ig) Ereceptors of sensitized mast cells leads to a release of proinflammatorymediators, including a number of vasoactive cytokines resulting in acuteallergic, or immediate (type I) hypersensitivity reactions [Gordon etal, Nature 346, 274-276 (1990) & Galli, N. Engl. J. Med., 328, 257-265(1993)]. A crucial role for JAK3 in IgE receptor-mediated mast cellresponses in vitro and in vivo has been established [Malaviya, et al,Biochem. Biophys. Res. Commun. 257, 807-813 (1999)]. In addition, theprevention of type I hypersensitivity reactions, including anaphylaxis,mediated by mast cell-activation through inhibition of JAK3 has alsobeen reported [Malaviya et al, J. Biol. Chem. 274, 27028-27038 (1999)].Targeting mast cells with JAK3 inhibitors modulated mast celldegranulation in vitro and prevented IgE receptor/antigen-mediatedanaphylactic reactions in vivo.

[0009] A recent study described the successful targeting of JAK3 forimmune suppression and allograft acceptance. The study demonstrated adose-dependent survival of Buffalo heart allograft in Wistar Furthrecipients upon administration of inhibitors of JAK3 indicating thepossibility of regulating unwanted immune responses in graft versus hostdisease [Kirken, Transpl. Proc. 33, 3268-3270 (2001)].

[0010] IL-4-mediated STAT-phosphorylation has been implicated as themechanism involved in early and late stages of rheumatoid arthritis(RA). Up-regulation of proinflammatory cytokines in RA synovium andsynovial fluid is a characteristic of the disease. It has beendemostrated that IL-4-mediated activation of IL-4/STAT pathway ismediated through the Janus Kinases (JAK 1 & 3) and that IL-4-associatedJAK kinases are expressed in the RA synovium [Muller-Ladner, et al, J.Immunol. 164, 3894-3901 (2000)].

[0011] Familial amyotrophic lateral sclerosis (FALS) is a fatalneurodegenerative disorder affecting about 10% of ALS patients. Thesurvival rates of FALS mice were increased upon treatment with a JAK3specific inhibitor. This suggested that JAK3 plays a role in FALS[Trieu, et al, Biochem. Biophys. Res. Commun. 267, 22-25 (2000)].

[0012] Signal transducer and activator of transcription (STAT) proteinsare activated by, among others, the JAK family kinases. Results form arecent study suggested the possibility of intervention in the JAK/STATsignaling pathway by targeting JAK family kinases with specificinhibitors for the treatment of leukemia [Sudbeck, et al, Clin. CancerRes. 5, 1569-1582 (1999)]. JAK3 specific compounds were shown to inhibitthe clonogenic growth of JAK3-expressing cell lines DAUDI, RAMOS,LC1;19, NALM-6, MOLT-3 and HL-60.

[0013] In animal models, TEL/JAK2 fusion proteins have inducedmyeloproliferative disorders and in hematopoietic cell lines,introduction of TEL/JAK2 resulted in activation of STAT1, STAT3, STAT5,and cytokine-independent growth [Schwaller, et al, EMBO J. 17, 5321-5333(1998)].

[0014] Inhibition of JAK 3 and TYK 2 abrogated tyrosine phosphorylationof STAT3, and inhibited cell growth of mycosis fungoides, a form ofcutaneous T cell lymphoma. These results implicated JAK family kinasesin the constitutively activated JAK/STAT pathway that is present inmycosis fungoides [Nielsen, et al, Proc. Nat. Acad. Sci. U.S.A. 94,6764-6769 (1997)]. Similarly, STAT3, STAT5, JAK1 and JAK2 weredemonstrated to be constitutively activated in mouse T cell lymphomacharacterized initially by LCK over-expression, thus further implicatingthe JAK/STAT pathway in abnormal cell growth [Yu, et al, J. Immunol.159, 5206-5210 (1997)]. In addition, IL-6-mediated STAT3 activation wasblocked by an inhibitor of JAK, leading to sensitization of myelomacells to apoptosis [Catlett-Falcone, et al, Immunity 10, 105-115(1999)].

[0015] Cyclin-dependent kinases (CDKs) are serine/threonine proteinkinases consisting of a β-sheet rich amino-terminal lobe and a largercarboxy-terminal lobe which is largely α-helical. The CDKs display the11 subdomains shared by all protein kinases and range in molecular massfrom 33 to 44 kD. This family of kinases, which includes CDK1, CKD2,CDK4, and CDK6, requires phosphorylation at the residue corresponding toCDK2 Thr160 in order to be fully active [Meijer, L., Drug ResistanceUpdates, 3, 83-88 (2000)].

[0016] Each CDK complex is formed from a regulatory cyclin subunit(e.g., cyclin A, B1, B2, D1, D2, D3, and E) and a catalytic kinasesubunit (e.g., CDK1, CDK2, CDK4, CDK5, and CDK6). Each differentkinase/cyclin pair functions to regulate the different and specificphases of the cell cycle known as the G1, S, G2, and M phases [Nigg, E.,Nature Reviews, 2, 21-32 (2001); Flatt, P., Pietenpol, J., DrugMetabolism Reviews, 32, 283-305 (2000)].

[0017] The CDKs have been implicated in cell proliferation disorders,particularly in cancer. Cell proliferation is a result of the direct orindirect deregulation of the cell division cycle and the CDKs play acritical role in the regulation of the various phases of this cycle. Forexample, the over-expression of cyclin D1 is commonly associated withnumerous human cancers including breast, colon, hepatocellularcarcinomas and gliomas [Flatt, P., Pietenpol, J., Drug MetabolismReviews, 32, 283-305 (2000)]. The CDK2/cyclin E complex plays a key rolein the progression from the early G₁ to S phases of the cell cycle andthe overexpression of cyclin E has been associated with various solidtumors. Therefore, inhibitors of cyclins D1, E, or their associated CDKsare useful targets for cancer therapy [Kaubisch, A., Schwartz, G., TheCancer Journal, 6, 192-212 (2000)].

[0018] CDKs, especially CDK2, also play a role in apoptosis and T-celldevelopment. CDK2 has been identified as a key regulator of thymocyteapoptosis [Williams, O., et al, European Journal of Immunology, 709-713(2000)]. Stimulation of CDK2 kinase activity is associated with theprogression of apoptosis in thymocytes, in response to specific stimuli.Inhibition of CDK2 kinase activity blocks this apoptosis resulting inthe protection of thymocytes.

[0019] In addition to regulating the cell cycle and apoptosis, the CDKsare directly involved in the process of transcription. Numerous virusesrequire CDKs for their replication process. Examples where CDKinhibitors restrain viral replication include human cytomegakovirus,herpes virus, and varicella-zoster virus [Meijer, L., Drug ResistanceUpdates, 3, 83-88 (2000)].

[0020] Inhibition of CDK is also useful for the treatment ofneurodegenerative disorders such as Alzheimer's disease. The appearanceof Paired Helical Filaments (PHF), associated with Alzheimer's disease,is caused by the hyperphosphorylation of Tau protein by CDK5/p25[Meijer, L., Drug Resistance Updates, 3, 83-88 (2000)].

[0021] JNK is a member of the mitogen-activated protein (MAP) kinasefamily. MAP kinases (MAPKs) are activated by a variety of signalsincluding growth factors, cytokines, UV radiation, and stress-inducingagents. MAPKs are serine/threonine kinases and their activation occur bydual phosphorylation of threonine and tyrosine at the Thr-X-Tyr segmentin the activation loop. MAPKs phosphorylate various substrates includingtranscription factors, which in turn regulate the expression of specificsets of genes and thus mediate a specific response to the stimulus.

[0022] Three distinct genes, JNK1, JNK2, JNK3 have been identified forthis kinase family and at least ten different splicing isoforms of JNKsexist in mammalian cells [Gupta et al., EMBO J., 15, 2760-70 (1996)].Members of the JNK family are activated by proinflammatory cytokines,such as tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β), aswell as by environmental stress, including anisomycin, UV irradiation,hypoxia, and osmotic shock [Minden et al., Biochemica et BiophysicaActa, 1333, F85-F104 (1997)].

[0023] The down-stream substrates of JNKs include transcription factorsc-Jun, ATF-2, Elk1, p53 and a cell death domain protein (DENN) [Zhang etal. Proc. Natl. Acad. Sci. USA, 95, 2586-91 (1998)]. Each JNK isoformbinds to these substrates with different affinities, suggesting aregulation of signaling pathways by substrate specificity of differentJNKs in vivo (Gupta et al., supra).

[0024] JNKs, along with other MAPKs, have been implicated in having arole in mediating cellular response to cancer, thrombin-induced plateletaggregation, immunodeficiency disorders, autoimmune diseases, celldeath, allergies, osteoporosis and heart disease. The therapeutictargets related to activation of the JNK pathway include chronicmyelogenous leukemia (CML), rheumatoid arthritis, asthma,osteoarthritis, ischemia, cancer and neurodegenerative diseases.

[0025] Several reports have detailed the importance of JNK activationassociated with liver disease or episodes of hepatic ischemia [Nat.Genet. 21, 326-9 (1999); FEBS Lett. 420, 201-4 (1997); J. Clin. Invest.102, 1942-50 (1998); Hepatology 28, 1022-30 (1998)]. Therefore,inhibitors of JNK may be useful to treat various hepatic disorders.

[0026] A role for JNK in cardiovascular disease such as myocardialinfarction or congestive heart failure has also been reported as it hasbeen shown JNK mediates hypertrophic responses to various forms ofcardiac stress [Circ. Res. 83, 167-78 (1998); Circulation 97, 1731-7(1998); J. Biol. Chem. 272, 28050-6 (1997); Circ. Res. 79, 162-73(1996); Circ. Res. 78, 947-53 (1996); J. Clin. Invest. 97, 508-14(1996)].

[0027] It has been demonstrated that the JNK cascade also plays a rolein T-cell activation, including activation of the IL-2 promoter. Thus,inhibitors of JNK may have therapeutic value in altering pathologicimmune responses [J. Immunol. 162, 3176-87 (1999); Eur. J. Immunol. 28,3867-77 (1998); J. Exp. Med. 186, 941-53 (1997); Eur. J. Immunol. 26,989-94 (1996)].

[0028] A role for JNK activation in various cancers has also beenestablished, suggesting the potential use of JNK inhibitors in cancer.For example, constitutively activated JNK is associated with HTLV-1mediated tumorigenesis [Oncogene 13, 135-42 (1996)]. JNK may play a rolein Kaposi's sarcoma (KS) because it is thought that the proliferativeeffects of bFGF and OSM on KS cells are mediated by their activation ofthe JNK signaling pathway [J. Clin. Invest. 99, 1798-804 (1997)]. Otherproliferative effects of other cytokines implicated in KS proliferation,such as vascular endothelial growth factor (VEGF), IL-6 and TNFα, mayalso be mediated by JNK. In addition, regulation of the c-jun gene inp210 BCR-ABL transformed cells corresponds with activity of JNK,suggesting a role for JNK inhibitors in the treatment for chronicmyelogenous leukemia (CML) [Blood 92, 2450-60 (1998)].

[0029] JNK1 and JNK2 are widely expressed in a variety of tissues. Incontrast, JNK3, is selectively expressed in the brain and to a lesserextent in the heart and testis [Gupta et al., supra; Mohit et al.,Neuron 14, 67-78 (1995); Martin et al., Brain Res. Mol. Brain Res. 35,47-57 (1996)]. JNK3 has been linked to neuronal apoptosis induced bykainic acid, indicating a role of JNK in the pathogenesis of glutamateneurotoxicity. In the adult human brain, JNK3 expression is localized toa subpopulation of pyramidal neurons in the CA1, CA4 and subiculumregions of the hippocampus and layers 3 and 5 of the neocortex [Mohit etal., supra]. The CA1 neurons of patients with acute hypoxia showedstrong nuclear JNK3-immunoreactivity compared to minimal, diffusecytoplasmic staining of the hippocampal neurons from brain tissues ofnormal patients [Zhang et al., supra]. Thus, JNK3 appears to be involvedinvolved in hypoxic and ischemic damage of CA1 neurons in thehippocampus.

[0030] In addition, JNK3 co-localizes immunochemically with neuronsvulnerable in Alzheimer's disease [Mohit et al., supra]. Disruption ofthe JNK3 gene caused resistance of mice to the excitotoxic glutamatereceptor agonist kainic acid, including the effects on seizure activity,AP-1 transcriptional activity and apoptosis of hippocampal neurons,indicating that the JNK3 signaling pathway is a critical component inthe pathogenesis of glutamate neurotoxicity (Yang et al., Nature, 389,,865-870 (1997)].

[0031] Based on these findings, JNK signalling, especially that of JNK3,has been implicated in the areas of apoptosis-driven neurodegenerativediseases such as Alzheimer's Disease, Parkinson's Disease, ALS(Amyotrophic Lateral Sclerosis), epilepsy and seizures, Huntington'sDisease, traumatic brain injuries, as well as ischemic and hemorrhagingstroke.

[0032] ZAP-70 is essential for T cell receptor signalling. Expression ofthis tyrosine kinase is restricted to T-cells and natural killer cells.The importance of ZAP-70 in T-cell function has been demonstrated inhuman patients, human T-cell lines and mice. Human patients sufferingfrom a rare form of severe combined deficiency syndrome (SCID) possesshomozygous mutations in ZAP-70 (reviewed in Elder J. of pedriatrichematology/oncology 19 (6) 546-550 1997). These patients have profoundimmunodeficiency, lack CD8+ T cells and have CD4+ T cells that areunresponsive to T cell receptor (TCR)-mediated stimulation. FollowingTCR activation these CD4+ cells show severe defects in Ca2+mobilization, tyrosine phosphorylation of down-stream substrates,proliferation and IL-2 production 70 (reviewed in Elder Pedriatricresearch 39, 743-748). Human Jurkat cells lacking ZAP-70 also provideimportant insights into the critical role of ZAP-70 in T cell receptorsignalling. A Jurkat clone (p116) with no detectable ZAP-70 protein wasshown to have defects in T cell receptor signalling which could becorrected by re-introduction of wt ZAP-70 (Williams et al Molecular andCellular Biology 18 (3), 1388-1399 1998). Studies of mice lacking ZAP-70also demonstrate a requirement of ZAP-70 in T-cell receptor signalling.Zap-70-deficient mice have profound defects in T cell development and Tcell receptor signalling in thymocytes is impaired (Negishi et al,Nature 376, 435-438 1995).

[0033] The importance of the kinase domain in ZAP-70 function isdemonstrated by studies of human patients and mice expressing identicalmutations in the DLAARN motif within the kinase domain of ZAP-70.Inactivation of kinase activity by this mutation results in defective Tcell receptor signalling (Elder et al J. Immunology 656-661 2001).Catalytically inactive ZAP-70 (Lys369Arg) was also defective inrestoring T cell receptor signalling in a ZAP-70 deficient Jurkat cellclone (p116) (Williams et al Molecular and Cellular Biology 18 (3),1388-1399 1998).

[0034] Accordingly, there is a great need to develop inhibitors of JAK,JNK, CDK, and ZAP-70 protein kinases that are useful in treating variousdiseases or conditions associated with JAK, JNK, CDK, and ZAP-70activation, particularly given the inadequate treatments currentlyavailable for the majority of these disorders.

SUMMARY OF THE INVENTION

[0035] It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of JAK, JNK, CDK, and ZAP-70 protein kinases. In certainembodiments, these compounds are effective as inhibitors of JAK3, JNK3,CDK2, and ZAP-70 protein kinases. These compounds have the generalformula I:

[0036] or a pharmaceutically acceptable salt thereof, wherein R¹, T,R^(X), m, Z¹, Z², Z³, Z⁴, Z⁵, Z⁶, and Z⁷ are as defined below.

[0037] These compounds and pharmaceutical compositions thereof areuseful for treating or preventing a variety of disorders, such as heartdisease, diabetes, Alzheimer's disease, immunodeficiency disorders,inflammatory diseases, allergic diseases, autoimmune diseases,destructive bone disorders such as osteoporosis, proliferativedisorders, infectious diseases, immunologically-mediated diseases, andviral diseases. The compositions are also useful in methods forpreventing cell death and hyperplasia and therefore may be used to treator prevent reperfusion/ischemia in stroke, heart attacks, and organhypoxia. The compositions are also useful in methods for preventingthrombin-induced platelet aggregation. The compositions are especiallyuseful for disorders such as chronic myelogenous leukemia (CML),rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer, liverdisease including hepatic ischemia, heart disease such as myocardialinfarction and congestive heart failure, pathologic immune conditionsinvolving T cell activation, and neurodegenerative disorders.

[0038] The compounds provided by this invention are also useful for thestudy of kinases in biological and pathological phenomena; the study ofintracellular signal transduction pathways mediated by such kinases, andthe comparative evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

[0039] I. General Description of Compounds of the Invention:

[0040] The present invention relates to a compound of formula I:

[0041] or a pharmaceutically acceptable salt thereof,

[0042] wherein:

[0043] R¹ is Q-Ar¹,

[0044] wherein Q is a C₁₋₂ alkylidene chain wherein one methylene unitof Q is optionally replaced by O, NR, NRCO, NRCONR, NRCO₂, CO, CO₂,CONR, OC(O)NR, SO₂, SO₂NR, NRSO₂, NRSO₂NR, C(O)C(O), or C(O)CH₂C(O);

[0045] Ar¹ is a 5-7 membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; wherein Ar¹ is optionally substituted with qindependent occurrences of Z—R^(Z); wherein q is 0-5, Z is a bond or isa C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene unitsof Z are optionally and independently replaced by CO, CO₂, COCO, CONR,OCONR, NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR,NRSO₂NR, O, S, or NR; and each occurrence of R^(Z) is independentlyselected from R′, halogen, NO₂, CN, OR′, SR′, N(R′)₂, NR′COR′,NR′CON(R′)₂, NR′CO₂R′, COR′, CO₂R′, OCOR′, CON(R′)₂, OCON(R′)₂, SOR′,SO₂R′, SO₂N(R′)₂, NR′SO₂R′, NR′SO₂N(R′)₂, COCOR′, or COCH₂COR′;

[0046] each occurrence of R is independently hydrogen or an optionallysubstituted C₁₋₆ aliphatic group; and each occurrence of R′ isindependently hydrogen or an optionally substituted C₁₋₆ aliphaticgroup, a 3-8-membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrencesof R′, are taken together with the atom(s) to which they are bound toform an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0047] Z¹ is N or CH;

[0048] Z⁷ is N or C(U)_(n)R^(Y);

[0049] T and U are each independently a bond or a saturated orunsaturated C₁₋₆ alkylidene chain, wherein up to two methylene units ofthe chain are optionally and independently replaced by CO, CO₂, COCO,CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR,NRSO₂NR, O, S, or NR;

[0050] m and n are each independently 0 or 1;

[0051] R^(X) and R^(Y) are each independently selected from R or Ar¹;

[0052] Z² is N or CR²; Z³ is N or CR³; Z⁴ is N or CR⁴; Z⁵ is N or CR⁵ ;and Z⁶ is N or CR⁶, wherein each occurrence of R², R³, R⁴, R⁵ or R⁶ isindependently R^(U) or (V)_(p)R^(V), provided that a) no more than threeof Z², Z³, Z⁴, Z⁵ or Z⁶ is N, and b) at least one of Z³, Z⁴ or Z⁵ isCR³, CR⁴, or CR⁵, respectively, and at least one of R³, R⁴, or R⁵ isR^(U),

[0053] each occurrence of R^(U) is NRCOR⁷, CONR(R⁷), SO₂NR(R⁷), NRSO₂R⁷,NRCONR(R⁷), NRSO₂NR(R⁷), or CONRNR(R⁷), wherein R⁷ is (CH₂)_(t)—Y—R⁸,and t is 0, 1, or 2, Y is a bond or is O, S, NR⁹, —OCH₂—, —SCH₂,—NR⁹CH₂, O(CH₂)₂—, —S(CH₂)₂, or —NR⁹ (CH₂)₂, and R⁸ is Ar², or R⁸ andR⁹, taken together with the nitrogen atom, form an optionallysubstituted 5-8 membered heterocyclyl or heteroaryl ring having 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0054] each occurrence of V is a bond or a saturated or unsaturated C₁₋₆alkylidene chain, wherein up to two methylene units of the chain areoptionally and independently replaced by CO, CO₂, COCO, CONR, OCONR,NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S,or NR;

[0055] each occurrence of p is 0 or 1;

[0056] each occurrence of R^(V) is R or Ar²; and

[0057] Ar² is a 5-7 membered saturated, partially unsaturated, or fullyunsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; wherein Ar² is optionally substituted with rindependent occurrences of W-R^(W); wherein r is 0-3, W is a bond or isa C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene unitsof W are optionally replaced by CO, CO₂, COCO, CONR, OCONR, NRNR,NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, orNR; and each occurrence of R^(W) is independently selected from R′,halogen, NO₂, CN, OR′, SR′, N(R′)₂, NR′COR′, NR′CON(R′)₂, NR′CO₂R′,COR′, CO₂R′, OCOR′, CON(R′)₂, OCON(R′)₂, SOR′, SO₂R′, SO₂N(R′)₂,NR′SO₂R′, NR′SO₂N(R′)₂, COCOR′, or COCH₂COR′;

[0058] provided that:

[0059] a) when Z¹ is N, Z⁷ is CH; and ring B is phenyl and at least oneof R³ or R⁴ is NHCOR⁷, then R¹ is not phenyl only substituted with twoor three occurrences of OR′; and

[0060] b) when Z¹ is N, Z⁷ is CH; and ring B is phenyl and at least oneof R³ of R⁴ is NHCOR⁷, SO₂R⁷, CONRR⁷, then R¹ is not phenyl onlysubstituted with one occurrence of —CON(R′)₂ in the para position.

[0061] In certain embodiments, for compounds of formula I describedgenerally above, and classes and subclasses thereof described herein,compounds where R¹ is phenyl substituted only by three occurrences ofOR′ are excluded.

[0062] In certain other embodiments, for the compounds of formula Idescribed generally above, and classes and subclasses thereof describedherein, compounds where R¹ is phenyl substituted only by two occurrencesof OR′ are excluded.

[0063] In yet other embodiments, for compounds of formula I describedgenerally above, and classes and subclasses thereof described herein,compounds where ring A is phenyl substituted in the meta position bynitro, fluorine-substituted lower alkoxy, or —NRCOR′ are excluded.

[0064] In certain other embodiments, for the compounds of formula Idescribed generally abbove, and classes and subclasses thereof describedherein, compounds where R¹ is phenyl substituted by nitro,fluorine-substituted lower alkoxy, or —NRCOR′ are excluded.

[0065] In still other embodiments, for compounds of formula I describedgenerally above, and classes and subclasses thereof described herein,compounds where (T)_(m)R^(x) is cyano are excluded.

[0066] In yet other embodiments, for compounds of formula I describedgenerally above, and classes and subclasses thereof described herein,compounds where (T)_(m)R^(x) is halogen are excluded.

[0067] In certain other embodiments, for compounds of formula Idescribed generally above, and classes and subclasses thereof describedherein, compounds where (T)_(m)R^(x) is alkynyl are excluded.

[0068] In yet other embodiments, for compounds of formula I describedgenerally above, and classes and subclasses thereof described herein,compounds where R¹ is 4-Me, 5-COOEt-thiazol-2-yl, ring B is4-NHCOOEt-phenyl, or 4-NHCOCF₃-phenyl, and Z⁷ is C-(4-OH-1-piperidinyl)are excluded.

[0069] 2. Compounds and Definitions:

[0070] Compounds of this invention include those described generallyabove, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

[0071] As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

[0072] The term “aliphatic” or “aliphatic group”, as used herein, meansa straight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-20 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-10aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-6 aliphatic carbon atoms, and in yet other embodimentsaliphatic groups contain 1-4 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic, that has a single point of attachment to therest of the molecule wherein any individual ring in said bicyclic ringsystem has 3-7 members. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0073] The term “heteroaliphatic”, as used herein, means aliphaticgroups wherein one or two carbon atoms are independently replaced by oneor more of oxygen, sulfur, nitrogen, phosphorus, or silicon.Heteroaliphatic groups may be substituted or unsubstituted, branched orunbranched, cyclic or acyclic, and include “heterocycle”,“heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.

[0074] The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”,or “heterocyclic” as used herein means non-aromatic, monocyclic,bicyclic, or tricyclic ring systems in which one or more ring membersare an independently selected heteroatom. In some embodiments, the“heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic”group has three to fourteen ring members in which one or more ringmembers is a heteroatom independently selected from oxygen, sulfur,nitrogen, or phosphorus, and each ring in the system contains 3 to 7ring members.

[0075] The term “heteroatom” means one or more of oxygen, sulfur,nitrogen, phosphorus, or silicon (including, any oxidized form ofnitrogen, sulfur, phosphorus, or silicon; the quaternized form of anybasic nitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

[0076] The term “unsaturated”, as used herein, means that a moiety hasone or more units of unsaturation.

[0077] The term “alkoxy”, or “thioalkyl”, as used herein, refers to analkyl group, as previously defined, attached to the principal carbonchain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

[0078] The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” meansalkyl, alkenyl or alkoxy, as the case may be, substituted with one ormore halogen atoms. The term “halogen” means F, Cl, Br, or I.

[0079] The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. The term“aryl” also refers to heteroaryl ring systems as defined hereinbelow.

[0080] The term “heteroaryl”, used alone or as part of a larger moietyas in “heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic, atleast one ring in the system contains one or more heteroatoms, andwherein each ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

[0081] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like)or heteroaryl (including heteroaralkyl and heteroarylalkoxy and thelike) group may contain one or more substituents and thus may be“optionally substituted”. Unless otherwise defined above and herein,suitable substituents on the unsaturated carbon atom of an aryl orheteroaryl group are generally selected from halogen; —R^(o); —OR^(o);—SR^(o); phenyl (Ph) optionally substituted with R^(o); —O(Ph)optionally substituted with R^(o); —(CH₂)₁₋₂ (Ph), optionallysubstituted with R^(o); —CH═CH(Ph), optionally substituted with R^(o);—NO₂; —CN; —N(R^(o))₂; —NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o);—NR^(o)C(O)N(R^(o))₂; —NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o);—NR^(o)NR^(o)C(O)R^(o); —NR^(o)NR^(o)C(O)N(R^(o))₂;—NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o); —CO₂R^(o);—C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂; —C(S)N(R^(o))₂; —OC(O)N(R^(o))₂;—OC(O)R^(o); —C(O)N(OR^(o)) R^(o); —C(NOR^(o)) R^(o); —S(O)₂R^(o);—S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o); —NR^(o)SO₂N(R^(o))₂;—NR^(o)SO₂R^(o); —N(OR^(o))R^(o); —C(═NH)—N(R^(o))₂; —P(O)₂R^(o);—PO(R^(o))₂; —OPO(R^(o))₂; —(CH₂)₀₋₂NHC(O)R^(o); phenyl (Ph) optionallysubstituted with R^(o); —O(Ph) optionally substituted with R^(o);—(CH₂)₁₋₂ (Ph), optionally substituted with R^(o); or —CH═CH(Ph),optionally substituted with R^(o); wherein each independent occurrenceof R^(o) is selected from hydrogen, optionally substituted C₁₋₆aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclicring, phenyl, —O(Ph), or —CH₂ (Ph), or, notwithstanding the definitionabove, two independent occurrences of R^(o), on the same substituent ordifferent substituents, taken together with the atom(s) to which eachR^(o) group is bound, to form an optionally substituted 3-12 memberedsaturated, partially unsaturated, or fully unsaturated monocyclic orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

[0082] Optional substituents on the aliphatic group of R^(o) areselected from NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen,C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂ (C₁₋₄aliphatic),O(haloC₁₋₄ aliphatic), or haloC₁₋₄aliphatic, wherein each of theforegoing C₁₋₄aliphatic groups of R^(o) is unsubstituted.

[0083] An aliphatic or heteroaliphatic group, or a non-aromaticheterocyclic ring may contain one or more substituents and thus may be“optionally substituted”. Unless otherwise defined above and herein,suitable substituents on the saturated carbon of an aliphatic orheteroaliphatic group, or of a non-aromatic heterocyclic ring areselected from those listed above for the unsaturated carbon of an arylor heteroaryl group and additionally include the following: ═O, ═S,═NNHR^(*), ═NN(R^(*))₂, ═NNHC(O)R^(*), ═NNHCO₂ (alkyl), ═NNHSO₂ (alkyl),or ═NR^(*), where each R^(*) is independently selected from hydrogen oran optionally substituted C₁₋₆ aliphatic group.

[0084] Unless otherwise defined above and herein, optional substituentson the nitrogen of a non-aromatic heterocyclic ring are generallyselected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺,—C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺¹)₂, —C(═NH)—N(R⁺)₂, or—NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an optionally substituted C₁₋₆aliphatic, optionally substituted phenyl, optionally substituted —O(Ph),optionally substituted —CH₂ (Ph), optionally substituted —(CH₂)₁₋₂ (Ph);optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 memberedheteroaryl or heterocyclic ring having one to four heteroatomsindependently selected from oxygen, nitrogen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R⁺,on the same substituent or different substituents, taken together withthe atom(s) to which each R⁺ group is bound, form an optionallysubstituted 3-12 membered saturated, partially unsaturated, or fullyunsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

[0085] Optional substituents on the aliphatic group or the phenyl ringof R⁺ are selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂,halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H, —CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic),wherein each of the foregoing C₁₋₄aliphatic groups of R⁺ isunsubstituted.

[0086] The term “alkylidene chain” refers to a straight or branchedcarbon chain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

[0087] As detailed above, in some embodiments, two independentoccurrences of R^(o) (or R⁺, R, R′ or any other variable similarlydefined herein), are taken together with the atom(s) to which they arebound to form an optionally substituted 3-12 membered saturated,partially unsaturated, or fully unsaturated monocyclic or bicyclic ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

[0088] Exemplary rings that are formed when two independent occurrencesof R^(o) (or R⁺, R, R′ or any other variable similarly defined herein),are taken together with the atom(s) to which each variable is boundinclude, but are not limited to the following: a) two independentoccurrences of R^(o) (or R⁺, R, R′ or any other variable similarlydefined herein) that are bound to the same atom and are taken togetherwith that atom to form a ring, for example, N(R^(o))₂, where bothoccurrences of R^(o) are taken together with the nitrogen atom to form apiperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) twoindependent occurrences of R^(o) (or R⁺, R, R′ or any other variablesimilarly defined herein) that are bound to different atoms and aretaken together with both of those atoms to form a ring, for examplewhere a phenyl group is substituted with two occurrences of OR^(o)

[0089] these two occurrences of R^(o) are taken together with the oxygenatoms to which they are bound to form a fused 6-membered oxygencontaining ring:

[0090] It will be appreciated that a variety of other rings can beformed when two independent occurrences of R^(o) (or R⁺, R, R′ or anyother variable similarly defined herein) are taken together with theatom(s) to which each variable is bound and that the examples detailedabove are not intended to be limiting.

[0091] Unless otherwise stated, structures depicted herein are alsomeant to include all isomeric (e.g., enantiomeric, diastereomeric, andgeometric (or conformational)) forms of the structure; for example, theR and S configurations for each asymmetric center, (Z) and (E) doublebond isomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

[0092] 3. Description of Exemplary Compounds:

[0093] In certain exemplary embodiments, Z¹ is N and amino pyrimidinesof general formula II are provided:

[0094] wherein R¹, (U)_(n)R^(Y), (T)_(m)R^(X), Z², Z³, Z⁴, Z⁵, and Z⁶are as defined generally above and in classes and subclasses herein.

[0095] In certain other exemplary embodiments, Z¹ is CH and aminopyridines of general formula III are provided:

[0096] wherein R¹, (U)_(n)R^(Y), (T)_(m)R^(X), Z², Z³, Z⁴, Z⁵, and Z⁶are as defined generally above and in classes and subclasses herein.

[0097] As described generally above, R¹ is Q-Ar¹. Certain exemplarysubstituents for R¹ include optionally substituted groups selected fromphenyl, cyclohexyl, cyclopentyl, pyridyl, morpholino, piperazinyl, orpiperidinyl. In other exemplary embodiments, R¹ is an optionallysubstituted group selected from phenyl, cyclohexyl, or pyridyl. In yetother embodiments, R¹ is optionally substituted phenyl.

[0098] As described generally above, in certain embodiments, Ar¹ issubstituted with q independent occurrences of ZR^(Z), where q is 0-5. Incertain embodiments, q is 0, 1, 2, or 3 and each independent occurrenceof ZR^(Z) is C₁₋₄alkyl, N(R′)₂, OR′, SR′, CON(R′)₂, NR′COR′, NR′SO₂R′,or SO₂N(R′)₂. In yet other embodiments, q is 1 and ZR^(Z) is —NH₂, —OH,C₁₋₄alkoxy, or —S(O)₂NH₂. In still other embodiments, q is 1, and ZR^(Z)is in the meta position and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or—S(O)₂NH₂.

[0099] Exemplary (T)_(m)R^(X) and (U)_(n)R^(Y) groups of formula I, andclasses and subclasses thereof as described herein, are hydrogen,halogen, NO₂, CN, OR, SR or N(R)₂, or C₁₋₄aliphatic optionallysubstituted with oxo, OR, SR, N(R)₂, halogen, NO₂ or CN. In someembodiments (T)_(m)R^(X) and (U)_(n)R^(Y) groups are hydrogen, Me, OH,OMe or N(R)₂. In other embodiments, (T)_(m)R^(X) and (U)_(n)R^(Y) areeach hydrogen.

[0100] In certain other preferred embodiments, ring B is one of therings i-xiv depicted below.

[0101] As detailed above, compounds of the invention relate to thosecompounds where at least one of Z³, Z⁴, or Z⁵ is CR³, CR⁴, or CR⁵respectively, and at least one of R³, R⁴, or R⁵ is NRCOR⁷, CONR(R⁷),SO₂NR(R⁷), NRSO₂R⁷, NRCONR(R⁷), NRSO₂NR(R⁷), or CONRNR(R⁷), wherein R⁷is (CH₂)_(t)—Y—R⁸, wherein t is 0, 1 or 2, wherein Y is a bond or is O,S, NR⁹, —OCH₂—, —SCH₂, —NR⁹CH₂, O(CH₂)₂—, —S(CH₂)₂, or —NR⁹ (CH₂)₂, andwherein R⁸ is Ar², or R⁸ and R⁹, taken together with the nitrogen atom,form a 5-8 membered heterocyclyl or heteroaryl ring having 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0102] In certain embodiments, t is 0, Y is a bond, and R⁸ is anoptionally substituted aryl or heteroaryl moiety. In other embodiments,t is 0, Y is a bond, and R⁸ is an optionally substituted heteroarylmoiety.

[0103] In yet other embodiments, R⁷ is —CH₂—Y—R⁸, and Y is NR⁹, O or S,and R⁸ is an optionally substituted aryl or heteroaryl moiety. In stillother embodiments, R⁸ is an optionally substituted aryl moiety.

[0104] In yet other embodiments, t is 0 or 1, Y is NR⁹, and R⁸ and R⁹,taken together with the nitrogen atom, form a 5-8 membered heterocyclylor heteroaryl ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

[0105] In still other embodiments, t is 0 or 1, Y is NR⁹, O, —NR⁹CH₂,—OCH₂—, —NR⁹ (CH₂)₂—, or —O(CH₂)₂— and R⁸ is an optionally substituted5-7 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0106] Certain exemplary R⁸ groups include 5- or 6-membered aryl orheteroaryl groups having one of the formulae:

[0107] In yet other embodiments, R⁸ is a 5- or 6-membered heteroarylgroup selected from:

[0108] Certain exemplary groups where R⁸ and R⁹, taken together with thenitrogen atom, form a 5-8 membered heterocyclyl or heteroaryl ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen orsulfur, include groups selected from:

[0109] In certain embodiments for each of the substituents describedgenerally above, r is 0, 1, 2, or 3. In other embodiments, r is 0, 1, or2. In still other embodiments, r is 0 or 1.

[0110] In certain embodiments, WR^(W) substituents are halogen,C₁₋₄alkyl, —(R)₂, —OR, —SR, —SO₂N(R)₂, —N(R)SO₂R, —N(R)COR, —N(R)₂,—CH₂OR, —CH₂N(R)₂, or —CH₂SR.

[0111] In certain embodiments, when t is 0 and Y is a bond, then R⁸ isan optionally substituted heteroaryl moiety selected from one of groupsb through r. In other embodiments, R⁸ is an optionally substitutedheteroaryl group b-i, k-i, or l-i.

[0112] In yet other embodiments, when t is 1, and Y is O, S or NR⁹, thenR⁸ is optionally substituted phenyl.

[0113] In still other embodiments, when t is 0 or 1, and Y is NR⁹, andR⁸ and R⁹, taken together form an optionally substituted group selectedfrom s, u or v. In yet other embodiments, R⁸ and R⁹, taken together,form an optionally substituted group s or v. In other embodiments, R⁸and R⁹, taken together form a group s or v, which group is substitutedwith one occurrence of —OH, or —CH₂OH.

[0114] It will be appreciated that for compounds as described above,certain additional compounds are of special interest. For example, incertain exemplary embodiments, for compounds of general formula IAabove, one class of compounds of special interest includes thosecompounds where Z³ or Z⁵ is CR³ or CR⁵, respectively, and R³ or R⁵ isNRC(O)R⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, wherein t is 0, 1 or 2, whereinY is a bond or is O, S, NR⁹, —OCH₂—, —SCH₂, —NR⁹CH₂, O(CH₂)₂—, —S(CH₂)₂,or —NR⁹ (CH₂)₂, and wherein R⁸ is Ar², or R⁸ and R⁹, taken together withthe nitrogen atom, form a 5-8 membered heterocyclyl or heteroaryl ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen orsulfur. It will be appreciated that compounds substituted at R³ and R⁵are equivalent and thus only compounds substituted at R³ are depictedbelow by formulas II-A and III-A.

[0115] It will be appreciated that for each of the compounds depicted byformulas II-A ring B is selected from a variety of aryl and heteroarylgroups. In certain, ring B is selected from i, ii, iii, iv, v, vii,viii, ix, x, xi, xii, or xiii and thus compounds of formulas II-A-i,II-A-ii, II-A-iii, II-A-iv, II-A-v, II-A-vii, II-A-viii, II-A-ix,II-A-x, II-A-xi, II-A-xii, or II-A-xiii are provided as depicted below:

[0116] It will be appreciated that for each of the compounds depicted byformulas III-A ring B is selected from a variety of aryl and heteroarylgroups. In certain embodiments, ring B is selected from i, ii, iii, iv,v, vii, viii, ix, x, xi, xii, or xiii and thus compounds of formulasIII-A-i, III-A-ii, III-A-iii, III-A-iv, III-A-v, III-A-vii, III-A-viii,III-A-ix, III-A-x, III-A-xi, III-A-xii, or III-A-xiii are provided asdepicted below:

[0117] Another class of compounds of special interest includes thosecompounds where Z⁴ is CR⁴, and R⁴ is —NRC(O)R⁷, wherein R⁷ is(CH₂)_(t)—Y—R⁸, wherein t is 0, 1 or 2, wherein Y is a bond or is O, S,NR⁹, —OCH₂—, —SCH₂, —NR⁹CH₂, O(CH₂)₂—, —S(CH₂)₂, or —NR⁹ (CH₂)₂, andwherein R⁸ is Ar², or R⁸ and R⁹, taken together with the nitrogen atom,form a 5-8 membered heterocyclyl or heteroaryl ring having 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0118] It will be appreciated that for each of the compounds depicted byformulas II-B ring B is selected from a variety of aryl and heteroarylgroups. In certain embodiments, ring B is selected from i, ii, iii, iv,vi, viii, ix, xii, or xiv and thus compounds of formulas II-B-i,II-B-ii, II-B-iii, II-B-iv, II-B-vi, II-B-viii, II-B-ix, II-B-xii, orII-B-xiv are provided as depicted below:

[0119] It will be appreciated that for each of the compounds depicted byformulas III-B ring B is selected from a variety of aryl and heteroarylgroups. In certain embodiments, ring B is selected from i, ii, iii, iv,vi, viii, ix, xii, or xiv and thus compounds of formulas III-B-i,III-B-ii, III-B-iii, III-B-iv, III-B-vi, III-B-viii, III-B-ix,III-B-xii, or III-B-xiv are provided as depicted below:

[0120] Yet another class of compounds of special interest includes thosecompounds where Z³ or Z⁵ is CR³ or CR⁵, respectively, and R³ or R⁵ isC(O)N(R)(R⁷), wherein R⁷ is (CH₂)_(t)—Y—R⁸, wherein t is 0, 1 or 2,wherein Y is a bond or is O, S, NR⁹, —OCH₂—, —SCH₂, —NR⁹CH₂, O(CH₂)₂—,—S(CH₂)₂, or —NR⁹ (CH₂)₂, and wherein R⁸ is Ar², or R⁸ and R⁹, takentogether with the nitrogen atom, form a 5-8 membered heterocyclyl orheteroaryl ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen or sulfur. It will be appreciated that because ofsymmetry considerations, compounds substituted at R³ and R⁵ areequivalent and thus only compounds substituted at R³ are depicted belowby formulas II-C and III-C.

[0121] It will be appreciated that for each of the compounds depicted byformulas II-C ring B is selected from a variety of aryl and heteroarylgroups. In certain embodiments, ring B is selected from i, ii, iii, iv,v, vii, viii, ix, x, xi, xii, or xiii and thus compounds of formulasII-C-i, II-C-ii, II-C-iii, II-C-iv, II-C-v, II-C-vii, II-C-viii,II-C-ix, II-C-x, II-C-xi, II-C-xii, or I-C-xiii are provided as depictedbelow:

[0122] It will be appreciated that for each of the compounds depicted byformulas III-C ring B is selected from a variety of aryl and heteroarylgroups. In certain embodiments, ring B is selected from i, ii, iii, iv,v, vii, viii, ix, x, xi, xii, or xiii and thus compounds of formulasIII-C-i, III-C-ii, III-C-iii, III-C-iv, III-C-v, III-C-vii, III-C-viii,III-C-ix, III-C-x, III-C-xi, III-C-xii, or III-C-xiii are provided asdepicted below:

[0123] Another class of compounds of special interest includes thosecompounds where Z⁴ is CR⁴, and R⁴ is C(O)N(R)(R⁷), wherein R⁷ is(CH₂)_(t)—Y—R⁸, wherein t is 0, 1 or 2, wherein Y is a bond or is O, S,NR⁹, —OCH₂—, —SCH₂, —NR⁹CH₂, O(CH₂)₂—, —S(CH₂)₂, or —NR⁹ (CH₂)₂, andwherein R⁸ is Ar², or R⁸ and R⁹, taken together with the nitrogen atom,form a 5-8 membered heterocyclyl or heteroaryl ring having 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0124] It will be appreciated that for each of the compounds depicted byformulas II-D ring B is selected from a variety of aryl and heteroarylgroups. In certain embodiments, ring B is selected from i, ii, iii, iv,vi, viii, ix, xii, or xiv and thus compounds of formulas II-D-i,II-D-ii, II-D-iii, II-D-iv, II-D-vi, II-D-viii, II-D-ix, II-D-xii, orII-D-xiv are provided as depicted below:

[0125] It will be appreciated that for each of the compounds depicted byformulas III-D ring B is selected from a variety of aryl and heteroarylgroups. In certain embodiments, ring B is selected from i, ii, iii, iv,vi, viii, ix, xii, or xiv and thus compounds of formulas III-D-i,III-D-ii, III-D-iii, III-D-iv, III-D-vi, III-D-viii, III-D-ix,III-D-xii, or III-D-xiv are provided as depicted below:

[0126] Certain subclasses of the foregoing compounds are described inmore detail below. It will be appreciated that, for each of thecompounds generally described above (formula I) and classes thereof,(e.g., formulas I, II-A, III-A, II-B, III-B, II-C, III-C, II-D, or III-Dand subsets thereof (e.g., II-A-i)), any combination of the subsets setforth below may be utilized to describe exemplary subclasses of theinvention. In particular, certain exemplary subsets include, but are notlimited to the following:

[0127] i) compounds where R¹ is an optionally substituted phenyl,cyclohexyl, cyclopentyl, pyridyl, morpholino, piperazinyl, orpiperidinyl group;

[0128] ii) compounds where R¹ is an optionally substituted phenyl,cyclohexyl, or pyridyl group;

[0129] iii) compounds where R¹ is optionally substituted phenyl;

[0130] iv) compounds where Ar¹ is substituted with q independentoccurrences of ZR^(Z), where q is 0-5, and each independent occurrenceof ZR^(Z) is C₁₋₄alkyl, N(R′)₂, OR′, SR′, CON(R′)₂, NR′COR′, NR′SO₂R′,or SO₂N(R′)₂;

[0131] v) compounds where q is 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or—SO₂NH₂;

[0132] vi) compounds where q is 1, and ZR^(Z) is in the meta positionand ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —SO₂NH₂;

[0133] vii) compounds where (T)_(m)R^(X) and (U)_(n)R^(Y) are hydrogen,halogen, NO₂, CN, OR, SR or N(R)₂, or C₁₋₄aliphatic optionallysubstituted with oxo, OR, SR, N(R)₂, halogen, NO₂ or CN;

[0134] viii) compounds where (T)_(m)R^(X) and (U)_(n)R^(Y) groups arehydrogen, Me, OH, OMe or N(R)₂;

[0135] ix) compounds where (T)_(m)R^(X) and (U)_(n)R^(Y) are eachhydrogen;

[0136] x) compounds where t is 0, Y is a bond, and R⁸ is an optionallysubstituted aryl or heteroaryl moiety;

[0137] xi) compounds where t is 0, Y is a bond, and R⁸ is an optionallysubstituted heteroaryl moiety;

[0138] xii) compounds where R⁷ is —CH₂—Y—R⁸, and Y is NR⁹, O or S, andR⁸ is an optionally substituted aryl or heteroaryl moiety;

[0139] xiii) compounds where R⁸ is an optionally substituted arylmoiety.

[0140] xiv) compounds where t is 0 or 1, Y is NR⁹, and R⁸ and R⁹, takentogether with the nitrogen atom, form an optionally substituted 5-8membered heterocyclyl or heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen or sulfur;

[0141] xv) compounds where R⁸ is a 5- or 6-membered aryl or heteroarylgroup having one of the formulae:

[0142] xvi) compounds where R⁸ is a 5- or 6-membered heteroaryl groupselected from:

[0143] xvii) compounds where R⁸ and R⁹, taken together with the nitrogenatom, form a group selected from:

[0144] xviii) compounds where r is 0, 1, 2, or 3;

[0145] xix) compounds where r is 0, 1, or 2;

[0146] xx) compounds where r is 0 or 1;

[0147] xxi) compounds where WR^(W) substituents are halogen, C₁₋₄alkyl,—(R)₂, —OR, —SR, —SO₂N(R)₂, —N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR,—CH₂N(R)₂, or —CH₂SR;

[0148] xxii) compounds where t is 0, Y is a bond, and R⁸ is anoptionally substituted heteroaryl moiety selected from one of groups bthrough r;

[0149] xxiii) compounds where t is 0, Y is a bond, and R⁸ is anoptionally substituted heteroaryl group b-i, k-i, or l-i;

[0150] xxiv) compounds where t is 1, and Y is O, S or NR⁹, then R⁸ isoptionally substituted phenyl;

[0151] xxv) compounds where t is 0 or 1, Y is NR⁹, and R⁸ and R⁹, takentogether form an optionally substituted group selected from s, u or v;

[0152] xxvi) compounds where R⁸ and R⁹, taken together, form anoptionally substituted group s or v;

[0153] xxvii) compounds where R⁸ and R⁹, taken together form a group sor v, which group is substituted with one occurrence of OH, or CH₂OH.

[0154] Certain other exemplary embodiments relate to those compoundswhere R¹ is optionally substituted phenyl and ring B is an optionallysubstituted phenyl group and compounds have one of the general formulaeIV or V:

[0155] In certain embodiments, for compounds described directly above,R³ is NRCOR⁷ and compounds have one of the general formulae IV-A-(i) orV-A-(i):

[0156] In certain other embodiments, for compounds described directlyabove, R⁴ is NRCOR⁷ and compounds have one of the general formulaeIV-B-(i) or V-B-(i):

[0157] In certain other embodiments, for compounds described directlyabove, R³ is CONRR⁷ and compounds have one of the general formulaeIV-C-(i) or V-C-(i):

[0158] In still other embodiments, for compounds described directlyabove, R⁴ is CONRR⁷ and compounds have one of the general formulaeIV-D-(i) or VII-D-(i):

[0159] It will be appreciated that each of ZR^(Z), q, U, R^(Y), T,R^(X), n, m, R², R³, R⁵, R⁶, R and R⁷ are each defined generally aboveand in classes, subclasses and species herein.

[0160] In other embodiments, R¹ is optionally substituted phenyl, ring Ais pyrimidinyl or pyridyl, ring B is phenyl, and R², R⁵, and R⁶ are eachhydrogen, and R³ and R⁴ are as defined generally and in classes,subclasses and species herein, and compounds have one of the generalformulae VI or VII:

[0161] Certain exemplary subsets for each of the compounds of formulasIV, V, VI and VII described above include those compounds where:

[0162] a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —SO₂NH₂;

[0163] b. R³ is NRCOR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 0, Y is abond, and R⁸ is an optionally substituted heteroaryl moiety selectedfrom one of groups b through r, and wherein r is 0 or 1, and WR^(W)substituents are halogen, C₁₋₄alkyl, —(R)₂, —OR, —SR, —SO₂N(R)₂,—N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR, —CH₂N(R)₂, or —CH₂SR; and

[0164] c. R⁴ is hydrogen.

[0165] Certain exemplary subsets for each of the compounds of formulasIV, V, VI and VII described above include those compounds where:

[0166] a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —SO₂NH₂;

[0167] b. R³ is CONRR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 0, Y is abond, and R⁸ is an optionally substituted heteroaryl moiety selectedfrom one of groups b through r, and wherein r is 0 or 1, and WR^(W)substituents are halogen, C ₁₋₄alkyl, —(R)₂, —OR, —SR, —SO₂N(R)₂,—N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR, —CH₂N(R)₂, or —CH₂SR; and

[0168] c. R⁴ is hydrogen.

[0169] Certain exemplary subsets for each of the compounds of formulasIV, V, VI and VII described above include those compounds where:

[0170] a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —SO₂NH₂;

[0171] b. R⁴ is NRCOR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 0, Y is abond, and R⁸ is an optionally substituted heteroaryl moiety selectedfrom one of groups b through r, and wherein r is 0 or 1, and WR^(W)substituents are halogen, C₁₋₄alkyl, —(R)₂, —OR, —SR, —SO₂N(R)₂,—N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR, —CH₂N(R)₂, or —CH₂SR; and

[0172] c. R³ is hydrogen.

[0173] Certain exemplary subsets for each of the compounds of formulasIV, V, VI and VII described above include those compounds where:

[0174] a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —SO₂NH₂;

[0175] b. R⁴ is CONRR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 0, Y is abond, and R⁸ is an optionally substituted heteroaryl moiety selectedfrom one of groups b through r, and wherein r is 0 or 1, and WR^(W)substituents are halogen, C₁₋₄alkyl, —(R)₂, —OR, —SR, —SO₂N(R)₂,—N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR, —CH₂N(R)₂, or —CH₂SR; and

[0176] c. R³ is hydrogen.

[0177] Certain exemplary subsets for each of the compounds of formulasIV, V, VI and VII described above include those compounds where:

[0178] a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —SO₂NH₂;

[0179] b. R³ is NRCOR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 1, Y isO, S or NR⁹, and R⁸ is an optionally substituted phenyl group, andwherein r is 0 or 1, and WR^(W) substituents are halogen, C₁₋₄alkyl,—(R)₂, —OR, —SR, —SO₂N(R)₂, —N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR,—CH₂N(R)₂, or —CH₂SR; and

[0180] c. R⁴ is hydrogen.

[0181] Certain exemplary subsets for each of the compounds of formulasIV, V, VI and VII described above include those compounds where:

[0182] a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —SO₂NH₂;

[0183] b. R³ is CONRR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 1, Y isO, S or NR⁹, and R⁸ is an optionally substituted phenyl group, andwherein r is 0 or 1, and WR^(W) substituents are halogen, C₁₋₄alkyl,—(R)₂, —OR, —SR, —SO₂N(R)₂, —N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR,—CH₂N(R)₂, or —CH₂SR; and

[0184] c. R⁴ is hydrogen.

[0185] Certain exemplary subsets for each of the compounds of formulasIV, V, VI and VII described above include those compounds where:

[0186] a. q is 0 or 1 and ZR^(Z) is —NH², —OH, C₁₋₄alkoxy, or —SO₂NH₂;

[0187] b. R⁴ is NRCOR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 1, Y isO, S or NR⁹, and R⁸ is an optionally substituted phenyl group, andwherein r is 0 or 1, and WR^(W) substituents are halogen, C₁₋₄alkyl,—(R)₂, —OR, —SR, —SO₂N(R)₂, —N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR,—CH₂N(R)₂, or —CH₂SR; and

[0188] c. R³ is hydrogen.

[0189] Certain exemplary subsets for each of the compounds of formulasIV, V, VI and VII described above include those compounds where:

[0190] a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —SO₂NH₂;

[0191] b. R⁴ is CONRR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 1, Y isO, S or NR⁹, and R⁸ is an optionally substituted phenyl group, andwherein r is 0 or 1, and WR^(W) substituents are halogen, C₁₋₄alkyl,—(R)₂, —OR, —SR, —SO₂N(R)₂, —N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR,—CH₂N(R)₂, or —CH₂SR; and

[0192] c. R³ is hydrogen.

[0193] Certain exemplary subsets for each of the compounds of formulasIV, V, VI and VII described above include those compounds where:

[0194] a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —SO₂NH₂;

[0195] b. R³ is NRCOR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 0 or 1, Yis NR⁹, and R⁸ and R⁹, taken together with the nitrogen atom, form agroup selected from s, t, u, or v, and wherein r is 0 or 1, and WR^(W)substituents are halogen, C₁₋₄alkyl, —(R)₂, —OR, —SR, —SO₂N(R)₂,—N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR, —CH₂N(R)₂, or —CH₂SR; and

[0196] c. R⁴ is hydrogen.

[0197] Certain exemplary subsets for each of the compounds of formulasIV, V, VI and VII described above include those compounds where:

[0198] a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —SO₂NH₂;

[0199] b. R³ is CONRR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 0 or 1, Yis NR⁹, and R⁸ and R⁹, taken together with the nitrogen atom, form agroup selected from s, t, u, or v, and wherein r is 0 or 1, and WR^(W)substituents are halogen, C₁₋₄alkyl, —(R)₂, —OR, —SR, —SO₂N(R)₂,—N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR, —CH₂N(R)₂, or —CH₂SR; and

[0200] c. R⁴ is hydrogen.

[0201] Certain exemplary subsets for each of the compounds of formulasIV, V, VI and VII described above include those compounds where:

[0202] a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —SO₂NH₂;

[0203] b. R⁴ is NRCOR⁷, wherein R⁷is (CH₂)_(t)—Y—R⁸, and t is 0 or 1, Yis NR⁹, and R⁸ and R⁹, taken together with the nitrogen atom, form agroup selected from s, t, u, or v, and wherein r is 0 or 1, and WR^(W)substituents are halogen, C₁₋₄alkyl, —(R)₂, —OR, —SR, —SO₂N(R)₂,—N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR, —CH₂N(R)₂, or —CH₂SR; and

[0204] c. R³ is hydrogen.

[0205] Certain exemplary subsets for each of the compounds of formulasIV, V, VI and VII described above include those compounds where:

[0206] a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —SO₂NH₂;

[0207] b. R⁴ is CONRR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 0 or 1, Yis NR⁹, and R⁸ and R⁹, taken together with the nitrogen atom, form agroup selected from s, t, u, or v, and wherein r is 0 or 1, and WR^(W)substituents are halogen, C₁₋₄alkyl, —(R)₂, —OR, —SR, —SO₂N(R)₂,—N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR, —CH₂N(R)₂, or —CH₂SR; and

[0208] c. R³ is hydrogen.

[0209] In other embodiments, for compounds of formulas IV, V, VI andVII, including those compounds described in preferred subsets directlyabove, q is 1, and ZR^(Z) is in the meta position and ZR^(Z) is —NH₂,—OH, C₁₋₄alkoxy, or —S(O)₂NH₂.

[0210] In yet other embodiments, for compounds of formulas IV, V, VI andVII, including those compounds described in preferred subsets directlyabove, when t is 0, and Y is a direct bond, R⁸ is from:

[0211] In still other embodiments, for compounds of formulas IV, V, VIand VII, including those compounds described in subsets directly above,when t is 0 or 1, and Y is NR⁹, then R⁸ and R⁹, taken together form anoptionally substituted group selected from s, u or v. In otherembodiments, R⁸ and R⁹, taken together, form an optionally substitutedgroup s or v. In yet other embodiments, R⁸ and R⁹, taken together form agroup s or v, which group is substituted with one occurrence of OH, orCH₂OH.

[0212] Representative examples of compounds of formula IV-A(i), IV-B(i),IV-C(i), IV-D(i), V-A(i), V-B(i), V-C(i), and V-D(i) are set forth belowin Tables 1, 2, 3, 4, 5, 6, 7 and 8. TABLE 1 Examples of Compounds ofFormula IV-A(i)

[0213] TABLE 2 Examples of Compounds of Formula IV-B(i)

[0214] TABLE 3 Examples of Compounds of Formula V-A(i):

[0215] TABLE 4 Examples of Compounds of Formula V-B(i)

[0216] TABLE 5 Examples of Compounds of Formula IV-C(i)

[0217] TABLE 6 Examples of Compounds of Formula IV-D(i)

[0218] TABLE 7 Examples of Compounds of Formula V-C(i)

[0219] TABLE 8 Examples of Compounds of Formula V-D(i)

[0220] III. General Synthetic Methodology:

[0221] The compounds of this invention may be prepared in general bymethods known to those skilled in the art for analogous compounds, asillustrated by the general schemes below, and the preparative examplesthat follow.

[0222] Scheme I below depicts a method for an exemplary synthesis forcertain compounds described herein where R³ or R⁴ is —NRCO(R⁷). Ingeneral, as depicted below, 3-aminoacetophenone (1) was reacted with anappropriate aryl chloride in the presence of ethyl-di-isopropylamine.The resulting amide (2) was then treated with dimethylfomamide-dimethylacetal (DMF-DMA) to generate the intermediate acryloyl (3). Subsequentreaction with a substituted phenylguanidine yields the desired compound.Compounds 1 and 2 and 3 are useful intermediates in forming a variety ofcompounds of formula I using methods known to one of skill in the artand as illustrated in the Examples below.

[0223] Scheme II is directed to certain exemplary compounds as describedherein. 3-aminoacetophenone (1′) was reacted with 2-furoyl chloride inthe presence of ethyl-di-isopropylamine. The resulting amide (2′) wasthen treated with dimethylfomamide-dimethyl acetal (DMF-DMA) to generatethe intermediate acryloyl (3′). Subsequent reaction with3-MeO-phenylguanidine yields the desired compound. Compounds 1′ and 2′and 3′ are useful intermediates in forming a variety of compounds offormula I using methods known to one of skill in the art and asillustrated in the Examples below.

[0224] Reagents: a. ClC(O)R⁷, i-Pr₂EtN; b. DMF-DMA (solvent), 100° C.;c. optionally substituted phenylguanidine, NaOMe, DMF, 100° C.

[0225] Reagents: a. 2-furoyl chloride, i-Pr₂EtN; b. DMF-DMA (solvent),100° C.; c. 3-MeO-phenylguanidine, NaOMe, DMF, 100° C.

[0226] Scheme III below depicts a method for an exemplary synthesis forcertain compounds described herein where R³ or R⁴ is —CONR(R⁷). In step(a), the enamine intermediate (6) is prepared by treating (5) withMe₂NC(OMe)₂H at reflux. The formation of the pyrimidine compound (8) atstep (b) is achieved by the treatment of enamine (6) with guanidine (7)at elevated temperature. The cyano group of intermediate (8) ishydrolized according to step (c) to form the carboxylic acid (9) whichis then treated with a variety of amines of formula R¹—NH₂ to form theamide compounds of formula (10). It would be apparent to one of skill inthe art that a wide variety of amines of formula R¹—NH₂ are amenable tocouple to the carboxylic acid (9) by methods known in the art.

[0227] Reagents and conditions: (a) Me₂NC(OMe)₂H, reflux, 12 hours; (b)CH₃CN, reflux, 12 hours; (c) conc. HCl, reflux, 12 hours; (d) H₂N—R¹,EDCI, HOBt, THF, 12 hours, RT.

[0228] 5. Uses, Formulation and Administration

[0229] Pharmaceutically Acceptable Compositions

[0230] As discussed above, the present invention provides compounds thatare inhibitors of protein kinases, and thus the present compounds areuseful for the treatment of diseases, disorders, and conditionsincluding, but not limited to a proliferative disorder, a cardiacdisorder, a neurodegenerative disorder, psychotic disorders, anautoimmune disorder, a condition associated with organ transplant, aninflammatory disorder, an immunologically mediated disorder, a viraldisease, or a bone disorder. In preferred embodiments, the compounds areuseful for the treatment of allergy, asthma, diabetes, Alzheimer'sdisease, Huntington's disease, Parkinson's disease, AIDS-associateddementia, amyotrophic lateral sclerosis (AML, Lou Gehrig's disease),multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy,reperfusion/ischemia (e.g., stroke), baldness, cancer, hepatomegaly,cardiovascular disease including cardiomegaly, cystic fibrosis, viraldisease, autoimmune diseases, atherosclerosis, restenosis, psoriasis,inflammation, hypertension, angina pectoris, cerebrovascularcontraction, peripheral circulation disorder, premature birth,arteriosclerosis, vasospasm (cerebral vasospasm, coronary vasospasm),retinopathy, erectile dysfunction (ED), AIDS, osteoporosis, Crohn'sDisease and colitis, neurite outgrowth, and Raynaud's Disease. Inpreferred embodiments, the disease, condition, or disorder isatherosclerosis, hypertension, erectile dysfunction (ED),reperfusion/ischemia (e.g., stroke), or vasospasm (cerebral vasospasmand coronary vasospasm).

[0231] Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

[0232] It will also be appreciated that certain of the compounds ofpresent invention can exist in free form for treatment, or whereappropriate, as a pharmaceutically acceptable derivative thereof.According to the present invention, a pharmaceutically acceptablederivative includes, but is not limited to, pharmaceutically acceptableprodrugs, salts, esters, salts of such esters, or any other adduct orderivative which upon administration to a patient in need is capable ofproviding, directly or indirectly, a compound as otherwise describedherein, or a metabolite or residue thereof.

[0233] As used herein, the term “pharmaceutically acceptable salt”refers to those salts which are, within the scope of sound medicaljudgement, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response andthe like, and are commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a JAK, JNK, CDK, and ZAP-70 kinase.

[0234] Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

[0235] As described above, the pharmaceutically acceptable compositionsof the present invention additionally comprise a pharmaceuticallyacceptable carrier, adjuvant, or vehicle, which, as used herein,includes any and all solvents, diluents, or other liquid vehicle,dispersion or suspension aids, surface active agents, isotonic agents,thickening or emulsifying agents, preservatives, solid binders,lubricants and the like, as suited to the particular dosage formdesired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W.Martin (Mack Publishing Co., Easton, Pa., 1980) discloses variouscarriers used in formulating pharmaceutically acceptable compositionsand known techniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

[0236] Uses of Compounds and Pharmaceutically Acceptable Compositions

[0237] In yet another aspect, a method for the treatment or lesseningthe severity of a proliferative disorder, a cardiac disorder, aneurodegenerative disorder, a psychotic disorder, an autoimmunedisorder, a condition associated with organ transplant, an inflammatorydisorder, an immunologically mediated disorder, a viral disease, or abone disorder is provided comprising administering an effective amountof a compound, or a pharmaceutically acceptable composition comprising acompound to a subject in need thereof. In certain embodiments of thepresent invention an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective fortreating or lessening the severity of a proliferative disorder, acardiac disorder, a neurodegenerative disorder, a psychotic disorder, anautoimmune disorder, a condition associated with organ transplant, aninflammatory disorder, an immunologically mediated disorder, a viraldisease, or a bone disorder. The compounds and compositions, accordingto the method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of a proliferative disorder, a cardiac disorder,a neurodegenerative disorder, an autoimmune disorder, a conditionassociated with organ transplant, an inflammatory disorder, animmunologically mediated disorder, a viral disease, or a bone disorder.The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. The compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

[0238] The pharmaceutically acceptable compositions of this inventioncan be administered to humans and other animals orally, rectally,parenterally, intracisternally, intravaginally, intraperitoneally,topically (as by powders, ointments, or drops), bucally, as an oral ornasal spray, or the like, depending on the severity of the infectionbeing treated. In certain embodiments, the compounds of the inventionmay be administered orally or parenterally at dosage levels of about0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about25 mg/kg, of subject body weight per day, one or more times a day, toobtain the desired therapeutic effect.

[0239] Liquid dosage forms for oral administration include, but are notlimited to, pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activecompounds, the liquid dosage forms may contain inert diluents commonlyused in the art such as, for example, water or other solvents,solubilizing agents and emulsifiers such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils(in particular, cottonseed, groundnut, corn, germ, olive, castor, andsesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. Besides inertdiluents, the oral compositions can also include adjuvants such aswetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

[0240] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

[0241] The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

[0242] In order to prolong the effect of a compound of the presentinvention, it is often desirable to slow the absorption of the compoundfrom subcutaneous or intramuscular injection. This may be accomplishedby the use of a liquid suspension of crystalline or amorphous materialwith poor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

[0243] Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

[0244] Solid dosage forms for oral administration include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound is mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and silicic acid, b) binders such as, forexample, carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such asglycerol, d) disintegrating agents such as agar--agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate, e) solution retarding agents such as paraffin, f)absorption accelerators such as quaternary ammonium compounds, g)wetting agents such as, for example, cetyl alcohol and glycerolmonostearate, h) absorbents such as kaolin and bentonite clay, and i)lubricants such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Inthe case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents.

[0245] Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugar as well as high molecular weight polyethyleneglycols and the like. The solid dosage forms of tablets, dragees,capsules, pills, and granules can be prepared with coatings and shellssuch as enteric coatings and other coatings well known in thepharmaceutical formulating art. They may optionally contain opacifyingagents and can also be of a composition that they release the activeingredient(s) only, or preferentially, in a certain part of theintestinal tract, optionally, in a delayed manner. Examples of embeddingcompositions that can be used include polymeric substances and waxes.Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polethylene glycols andthe like.

[0246] The active compounds can also be in micro-encapsulated form withone or more excipients as noted above. The solid dosage forms oftablets, dragees, capsules, pills, and granules can be prepared withcoatings and shells such as enteric coatings, release controllingcoatings and other coatings well known in the pharmaceutical formulatingart. In such solid dosage forms the active compound may be admixed withat least one inert diluent such as sucrose, lactose or starch. Suchdosage forms may also comprise, as is normal practice, additionalsubstances other than inert diluents, e.g., tableting lubricants andother tableting aids such a magnesium stearate and microcrystallinecellulose. In the case of capsules, tablets and pills, the dosage formsmay also comprise buffering agents. They may optionally containopacifying agents and can also be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain part of theintestinal tract, optionally, in a delayed manner. Examples of embeddingcompositions that can be used include polymeric substances and waxes.

[0247] Dosage forms for topical or transdermal administration of acompound of this invention include ointments, pastes, creams, lotions,gels, powders, solutions, sprays, inhalants or patches. The activecomponent is admixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives or buffers as may berequired. Ophthalmic formulation, ear drops, and eye drops are alsocontemplated as being within the scope of this invention. Additionally,the present invention contemplates the use of transdermal patches, whichhave the added advantage of providing controlled delivery of a compoundto the body. Such dosage forms can be made by dissolving or dispensingthe compound in the proper medium. Absorption enhancers can also be usedto increase the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

[0248] As described generally above, the compounds of the invention areuseful as inhibitors of protein kinases. In one embodiment, thecompounds and compositions of the invention are inhibitors of one ormore of JAK, JNK, CDK, and ZAP-70, and thus, without wishing to be boundby any particular theory, the compounds and compositions areparticularly useful for treating or lessening the severity of a disease,condition, or disorder where activation of one or more of JAK, JNK, CDK,and ZAP-70 is implicated in the disease, condition, or disorder. Whenactivation of JAK, JNK, CDK, and ZAP-70 is implicated in a particulardisease, condition, or disorder, the disease, condition, or disorder mayalso be referred to as “JAK, JNK, CDK, and ZAP-70-mediated disease” ordisease symptom. Accordingly, in another aspect, the present inventionprovides a method for treating or lessening the severity of a disease,condition, or disorder where activation or one or more of JAK, JNK, CDK,and ZAP-70 is implicated in the disease state.

[0249] The activity of a compound utilized in this invention as aninhibitor of JAK, JNK, CDK, and ZAP-70, may be assayed in vitro, in vivoor in a cell line. In vitro assays include assays that determineinhibition of either the phosphorylation activity or ATPase activity ofactivated JAK, JNK, CDK, and ZAP-70. Alternate in vitro assaysquantitate the ability of the inhibitor to bind to JAK, JNK, CDK, andZAP-70. Inhibitor binding may be measured by radiolabelling theinhibitor prior to binding, isolating the inhibitor/JAK, inhibitor/JNK,inhibitor/CDK, or inhibitor/ZAP-70 complex and determining the amount ofradiolabel bound. Alternatively, inhibitor binding may be determined byrunning a competition experiment where new inhibitors are incubated withJAK, JNK, CDK, and ZAP-70 bound to known radioligands.

[0250] The term “measurably inhibit”, as used herein means a measurablechange in JAK, JNK, CDK, and ZAP-70 activity between a sample comprisingsaid composition and a JAK, JNK, CDK, and ZAP-70 kinase and anequivalent sample comprising JAK, INK, CDK, and ZAP-70 kinase in theabsence of said composition.

[0251] The term “JAK-mediated disease”, as used herein means any diseaseor other deleterious condition in which a JAK family kinase is known toplay a role. Such conditions include, without limitation, immuneresponses such as allergic or type I hypersensitivity reactions, asthma,autoimmune diseases such as transplant rejection, graft versus hostdisease, rheumatoid arthritis, amyotrophic lateral sclerosis, andmultiple sclerosis, neurodegenerative disorders such as Familialamyotrophic lateral sclerosis (FALS), as well as in solid andhematologic malignancies such as leukemias and lymphomas.

[0252] According to another embodiment, the invention provides a methodfor treating or lessening the severity of a CDK2-mediated disease orcondition in a patient comprising the step of administering to saidpatient a composition according to the present invention.

[0253] The term “CDK2-mediated disease”, as used herein means anydisease or other deleterious condition in which CDK2 is known to play arole. Accordingly, these compounds are useful for treating diseases orconditions that are known to be affected by the activity of CDK2 kinase.Such diseases or conditions include cancer, Alzheimer's disease,restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV,herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseasessuch as rheumatoid arthritis, viral infections, neurodegenerativedisorders, disorders associated with thymocyte apoptosis, orproliferative disorders resulting from the deregulation of the cellcycle, especially of the progression from G₁ to S phase.

[0254] According to another embodiment, the invention provides a methodfor treating or lessening the severity of a CDK2-mediated disease orcondition in a patient comprising the step of administering to saidpatient a composition according to the present invention.

[0255] The term “JNK-mediated condition”, as used herein means anydisease or other deleterious condition in which JNK is known to play arole. Such conditions include, without limitation, inflammatorydiseases, autoimmune diseases, destructive bone disorders, proliferativedisorders, cancer, infectious diseases, neurodegenerative diseases,allergies, reperfusion/ischemia in stroke, heart attacks, angiogenicdisorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy,thrombin-induced platelet aggregation, and conditions associated withprostaglandin endoperoxidase synthase-2 .

[0256] “JNK-mediated conditions” also include ischemia/reperfusion instroke, heart attacks, myocardial ischemia, organ hypoxia, vascularhyperplasia, cardiac hypertrophy, hepatic ischemia, liver disease,congestive heart failure, pathologic immune responses such as thatcaused by T cell activation and thrombin-induced platelet aggregation.

[0257] In addition, JNK inhibitors of the instant invention may becapable of inhibiting the expression of inducible pro-inflammatoryproteins. Therefore, other “JNK-mediated conditions” which may betreated by the compounds of this invention include edema, analgesia,fever and pain, such as neuromuscular pain, headache, cancer pain,dental pain and arthritis pain.

[0258] According to another embodiment, the invention provides a methodfor treating or lessening the severity of a ZAP-70-mediated disease orcondition in a patient comprising the step of administering to saidpatient a composition according to the present invention.

[0259] The term “ZAP-70-mediated condition”, as used herein means anydisease or other deleterious condition in which ZAP-70 is known to playa role. Such conditions include, without limitation, autoimmune,inflammatory, proliferative and hyperproliferative diseases andimmunologically-mediated diseases including rejection of transplantedorgans or tissues and Acquired Immunodeficiency Syndrome (AIDS).

[0260] For example, ZAP-70-mediated conditions include diseases of therespiratory tract including, without limitation, reversible obstructiveairways diseases including asthma, such as bronchial, allergic,intrinsic, extrinsic and dust asthma, particularly chronic or inveterateasthma (e.g. late asthma airways hyper-responsiveness) and bronchitis.Additionally, ZAP-70 diseases include, without limitation, thoseconditions characterised by inflammation of the nasal mucus membrane,including acute rhinitis, allergic, atrophic thinitis and chronicrhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitispurulenta, rhinitis sicca and rhinitis medicamentosa; membranousrhinitis including croupous, fibrinous and pseudomembranous rhinitis andscrofoulous rhinitis, seasonal rhinitis including rhinitis nervosa (hayfever) and vasomotor rhinitis, sarcoidosis, farmer's lung and relateddiseases, fibroid lung and idiopathic interstitial pneumonia.

[0261] ZAP-70-mediated conditions also include diseases of the bone andjoints including, without limitation, (pannus formation in) rheumatoidarthritis, seronegative spondyloarthropathis (including ankylosingspondylitis, psoriatic arthritis and Reiter's disease), Behcet'sdisease, Sjogren's syndrome and systemic sclerosis.

[0262] ZAP-70-mediated conditions also include diseases and disorders ofthe skin, including, without limitation, psoriasis, systemic sclerosis,atopical dermatitis, contact dermatitis and other eczmatous dermitides,seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus,epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas,cutaneous eosinophilias, uveitis, Alopecia, areata and vernalconjunctivitis.

[0263] ZAP-70-mediated conditions also include diseases and disorders ofthe gastrointestinal tract, including, without limitation, Coeliacdisease, proctitis, eosinophilic gastro-enteritis, mastocytosis,pancreatitis, Crohn's disease, ulcerative colitis, food-relatedallergies which have effects remote from the gut, e.g. migraine, rhinitsand eczema.

[0264] ZAP-70-mediated conditions also include those diseases anddisorders of other tissues and systemic disease, including, withoutlimiation, multiple scleroris, artherosclerosis, acquiredimmunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus,erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type Idiabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome,lepromatous leprosy, sezary syndrome and idiopathic thrombocytopeniapupura, restenosis following angioplasty, tumours (for example leukemia,lymphomas), artherosclerosis, and systemic lupus erythematosus.

[0265] ZAP-70-mediated conditions. also include allograft rejectionincluding, without limitation, acute and chronic allograft rejectionfollowing for example transplantation of kidney, heart, liver, lung,bone marrow, skin and cornea; and chronic graft versus host disease.

[0266] It will also be appreciated that the compounds andpharmaceutically acceptable compositions of the present invention can beemployed in combination therapies, that is, the compounds andpharmaceutically acceptable compositions can be administeredconcurrently with, prior to, or subsequent to, one or more other desiredtherapeutics or medical procedures. The particular combination oftherapies (therapeutics or procedures) to employ in a combinationregimen will take into account compatibility of the desired therapeuticsand/or procedures and the desired therapeutic effect to be achieved. Itwill also be appreciated that the therapies employed may achieve adesired effect for the same disorder (for example, an inventive compoundmay be administered concurrently with another agent used to treat thesame disorder), or they may achieve different effects (e.g., control ofany adverse effects). As used herein, additional therapeutic agents thatare normally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

[0267] For example, chemotherapeutic agents or other anti-proliferativeagents may be combined with the compounds of this invention to treatproliferative diseases and cancer. Examples of known chemotherapeuticagents include, but are not limited to, For example, other therapies oranticancer agents that may be used in combination with the inventiveanticancer agents of the present invention include surgery, radiotherapy(in but a few examples, gamma.-radiation, neutron beam radiotherapy,electron beam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes, to name a few), endocrine therapy, biologicresponse modifiers (interferons, interleukins, and tumor necrosis factor(TNF) to name a few), hyperthermia and cryotherapy, agents to attenuateany adverse effects (e.g., antiemetics), and other approvedchemotherapeutic drugs, including, but not limited to, alkylating drugs(mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan,Ifosfamide), antimetabolites (Methotrexate), purine antagonists andpyrimidine antagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile,Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine,Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan),antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas(Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin),enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide,and Megestrol), Gleevec™, adriamycin, dexamethasone, andcyclophosphamide. For a more comprehensive discussion of updated cancertherapies see, http://www.nci.nih.gov/, a list of the FDA approvedoncology drugs at http://www.fda.gov/cder/cancer/druglistframe.htm, andThe Merck Manual, Seventeenth Ed. 1999, the entire contents of which arehereby incorporated by reference.

[0268] Other examples of agents the inhibitors of this invention mayalso be combined with include, without limitation: treatments forAlzheimer's Disease such as Aricept® and Excelon® ; treatments forParkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole,pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine;agents for treating Multiple Sclerosis (MS) such as beta interferon(e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments forasthma such as albuterol and Singulair®; agents for treatingschizophrenia such as zyprexa, risperdal, seroquel, and haloperidol;anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA,azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

[0269] The amount of additional therapeutic agent present in thecompositions of this invention will be no more than the amount thatwould normally be administered in a composition comprising thattherapeutic agent as the only active agent. Preferably the amount ofadditional therapeutic agent in the presently disclosed compositionswill range from about 50% to 100% of the amount normally present in acomposition comprising that agent as the only therapeutically activeagent.

[0270] The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating implantable medical devices, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device.

[0271] Vascular stents, for example, have been used to overcomerestenosis (re-narrowing of the vessel wall after injury). However,patients using stents or other implantable devices risk clot formationor platelet activation. These unwanted effects may be prevented ormitigated by pre-coating the device with a pharmaceutically acceptablecomposition comprising a kinase inhibitor. Suitable coatings and thegeneral preparation of coated implantable devices are described in U.S.Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

[0272] Another aspect of the invention relates to inhibiting JAK, JNK,CDK, and ZAP-70 activity in a biological sample or a patient, whichmethod comprises administering to the patient, or contacting saidbiological sample with a compound of formula I or a compositioncomprising said compound. The term “biological sample”, as used herein,includes, without limitation, cell cultures or extracts thereof;biopsied material obtained from a mammal or extracts thereof; and blood,saliva, urine, feces, semen, tears, or other body fluids or extractsthereof.

[0273] Inhibition of JAK, JNK, CDK, and ZAP-70 kinase activity in abiological sample is useful for a variety of purposes that are known toone of skill in the art. Examples of such purposes include, but are notlimited to, blood transfusion, organ-transplantation, biologicalspecimen storage, and biological assays.

EXAMPLES Example 1

[0274]

[0275] Furan-2-carboxylic Acid (3-acetyl-phenyl)-amide.

[0276] To a solution of 1 g of 3-aminoacetophenone in 20 mL of CH₂Cl₂was added 5 mL of ethyl-di-iso-propylamine. To the stirred reactionmixture was then added 1 mL of 2-furoyl chloride which was allowed tostir at 25° C. for 8 h. The reaction mixture was concentrated in vacuoand the residue was purified by silica gel chromatography (CH₂Cl₂) toyield 900 mg of furan-2-carboxylic acid (3-acetyl-phenyl)-amide as awhite solid. ¹H NMR (CDCl₃, 500 MHz) δ 8.11 (1 H, br s), 8.09 (1H, t,J=2 Hz), 7.93 (1 H, m), 7.66 (1H, m), 7.47 (1 H, m), 7.20 (1 H, m), 6.52(1 H, m), 2.56 (3H, s) ppm.

Example 2

[0277]

[0278] Furan-2-carboxylic Acid[3-(3-dimethylamino-acryloyl)-phenyl]-methyl-amide andFuran-2-carboxylic Acid [3-(3-dimethylamino-acryloyl)-phenyl]-amide.

[0279] A 25 mL round bottomed flask equipped with a stirbar was chargedwith 300 mg of furan-2-carboxylic acid (3-acetyl-phenyl)-amide as asolution in 5 mL of dimethylformamide-dimethyl acetal (DMF-DMA). Theresulting reaction mixture was warmed to 100° C. for 8 h. The excessDMF-DMA was removed in vacuo, and the residue was pushed through a plugof silica (Ethanol) to provide an inseparable mixture offuran-2-carboxylic acid[3-(3-dimethylamino-acryloyl)-phenyl]-methyl-amide andfuran-2-carboxylic acid [3-(3-dimethylamino-acryloyl)-phenyl]-amide as adark yellow oil (200 mg) which was used without further purification.

Example 3

[0280]

[0281] Furan-2-carboxylic Acid{3-[2-(3-methoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-amide andFuran-2-carboxylic Acid{3-[2-(3-methoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-methyl-amide.

[0282] To a 25 mL round bottomed flask equipped with a stirbar was added200 mg of furan-2-carboxylic acid[3-(3-dimethylamino-acryloyl)-phenyl]-methyl-amide andfuran-2-carboxylic acid [3-(3-dimethylamino-acryloyl)-phenyl]-amide as asolution in 5 mL of DMF. To the stirred reaction was added sequentially180 mg of 3-methoxylphenylguanidine and 200 mg of sodium methoxide. Theresulting reaction mixture was allowed to stir at 100° C. for 8 h. Thereaction mixture was poured into water (50 mL) and extracted with 2×50mL of EtOAc. The organic layers were combined, dried over Na₂SO₄, andconcentrated to a yellow oil which was purified by silica gelchromatography (8:1 CH₂Cl₂:EtOH) to yield 25 mg of furan-2-carboxylicacid {3-[2-(3-methoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-amide and 25mg of and 25 mg furan-2-carboxylic acid{3-[2-(3-methoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-methyl-amide.

Example 4

[0283]

[0284] Furan-2-carboxylic Acid{3-[2-(3-methoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-amide

[0285]¹H NMR (CDCl₃, 500 MHz): δ 8.40 (1 H, d, J=5 Hz), 8.29 (1H, t, J=2Hz), 8.16 (1 H, s), 7.77 (2 H, m), 7.48 (1H, t, J=2 Hz), 7.40 (1 H, t,J=8 Hz), 7.30 (1 H, s), 7.19 (2 H, m), 7.08 (2 H, m), 6.53 (2 H, m),3.77 (3 H, s) ppm. HPLC(purity, RT): >99% purity, 3.140 min. MS (FIA):387.3 (M+H)

Example 5

[0286]

[0287] Furan-2-carboxylic Acid{3-[2-(3-methoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-methyl-amide.

[0288]¹H NMR (CDCl₃, 500 MHz): δ 8.42 (1 H, d, J=5 Hz), 7.99 (1H, d, J=8Hz), 7.93 (1 H, t, J=2 Hz), 7.47 (2 H, m), 7.24 (3 H, m), 7.17 (2 H, t,J=8 Hz), 7.05 (2 H, m), 6.55 (1 H, m), 6.14 (1 H, m), 5.99 (1 H, m),3.75 (3 H, s), 3.43 (3 H, s) ppm. HPLC(purity, RT): >99% purity, 3.157min. MS (FIA): 401.3 (M+H).

Example 6

[0289]

[0290] Furan-2-carboxylic Acid{3-[2-(3-hydroxy-phenylamino)-pyrimidin-4-yl]-phenyl}-amide:

[0291]¹H NMR (CDCl₃, 500 MHz): δ 8.42 (1 H, d, J=5 Hz), 7.99 (1H, d, J=8Hz), 7.93 (1 H, t, J=2 Hz), 7.47 (2 H, m), 7.24 (3 H, m), 7.17 (2 H, t,J=8 Hz), 7.05 (2 H, m), 6.55 (1 H, m), 6.14 (1 H, m), 5.99 (1 H, m),3.75 (3 H, s), 3.43 (3 H, s) ppm. HPLC(purity, RT): >99% purity, 3.289min. MS (FIA): 373.3 (M+H)

Example 7

[0292]

[0293] Furan-2-carboxylic Acid{3-[2-(3-sulfamoyl-phenylamino)-pyrimidin-4-yl]-phenyl}-amide

[0294]¹H NMR (DMSO-d₆, 500 MHz): δ 9.21 (1 H, s), 8.93 (1H, s), 8.61 (1H, s), 8.52 (1 H, d, J=6 Hz), 8.17 (1 H, d, J=6 Hz), 7.95 (1 H, t, J=3Hz), 7.75 (1 H, m),7.65-7.27 (8H, m),6.66 (2 H, m) ppm. HPLC(purity,RT): >99% purity, 3.250 min. MS (FIA): 436.2 (M+H)

Example 8

[0295]

[0296] Thiophene-2-carboxylicAcid{3-[2-(3-amino-phenylamino)-pyrimidin-4-yl]-phenyl}-amide:

[0297]¹H NMR (DMSO-d₆, 500 MHz): δ 10.79 (1H, s), 10.08 (1 H, s), 8.74(1 H, s), 8.62 (1 H, d, J=5 Hz), 8.37 (1 H, d, J=3 Hz), 8.27 (1 H, s),8.03 (1 H, d, J=8 Hz), 7.90 (2H, d, J=4 Hz), 7.73 (1 H, d, J=8 Hz), 7.54(1 H, t, J=8 Hz), 7.46-7.41 (2 H, m), 7.25 (1 H, t, J=4 Hz), 7.0 (1 H,d, J=8 Hz) ppm. HPLC(purity, RT): >99% purity, 2.57 min. MS (FIA): 388.3(M+H).

Example 9

[0298]

[0299] Pyridine-2-carboxylic Acid{3-[2-(3-amino-phenylamino)-pyrimidin-4-yl]-phenyl}-amide:

[0300]¹H NMR (CDCl₃, 500 MHz): δ 10.11 (1 H, s), 9.02 (1H, s), 8.56 (1H, d, J=4 Hz), 8.39 (1 H, d, J=5 Hz), 8.19 (1 H, d, J=8 Hz), 7.86-7.76(1 H, m), 7.70 (1 H, d, J=8 Hz), 7.53 (1 H, d, J=7 Hz), 7.44-7.39 (2 H,m), 7.20 (1 H, d, J=8 Hz), 7.13 (1 H, d, J=5 Hz), 7.02 (1 H, t, J=8 Hz),6.60 (1 H, d, J=7 Hz), 6.32 (1 H, d, J=7 Hz) ppm. HPLC(purity, RT): 95%purity, 2.862 min. MS (FIA): 383.3 (M+H).

Example 10

[0301]

[0302] Furan-2-carboxylic Acid{4-[2-(3-amino-phenylamino)-pyrimidin-4-yl]-phenyl}-amide:

[0303]¹H NMR (TFA, 500 MHz): δ 7.69 (1 H, s), 7.53 (2 H, br s), 7.34 (1H, br s), 7.19 (2 H, br s), 7.10 (1 H, br s), 6.94 (1 H, br s), 6.89 (2H, br s), 6.77 (1 H, m), 6.70 (1 H, m), 5.91 (1 H, m) ppm. HPLC(purity,RT): >99% purity, 2.619 min. MS (FIA): 373.3 (M+H).

Example 11

[0304]

[0305] Thiophene-2-carboxylic Acid{4-[2-(3-hydroxy-phenylamino)-pyrimidin-4-yl]-phenyl}-amide:

[0306]¹H NMR (CDCl₃, 500 MHz): δ 9.79 (1 H, s), 8.90 (1H, s), 8.59 (1 H,s), 8.37 (1 H, s), 8.28 (1 H, s), 7.64 (1 H, d, J=8 Hz), 7.51 (1 H, s),7.38 (1 H, t, J=8 Hz), 7.32 (1 H, d, J=3 Hz), 7.16 (1 H, d, J=5 Hz),7.11-7.06 (2 H, m), 6.56-6.54 (2 H, m), 6.40 (1 H, d, J=5 Hz) ppm.HPLC(purity, RT): >99% purity, 3.417 min. MS (FIA): 389.2 (M+H).

Example 12

[0307]

[0308] Thiophene-2-carboxylic Acid{4-[2-(3-amino-phenylamino)-pyrimidin-4-yl]-phenyl}-amide:

[0309]¹H NMR (DMSO-d₆, 500 MHz): δ 10.79 (1H, s), 10.08 (1 H, s), 8.74(1 H, s), 8.62 (1 H, d, J=5 Hz), 8.37 (1 H, d, J=3 Hz), 8.27 (1 H, s),8.03 (1 H, d, J=8 Hz), 7.90 (2 H, d, J=4 Hz), 7.73 (1 H, d, J=8 Hz),7.54 (1 H, t, J=8 Hz), 7.46-7.41 (2 H, m), 7.25 (1 H, t, J=4 Hz), 7.0 (1H, d, J=8 Hz) ppm. HPLC(purity, RT): >99% purity, 2.739 min. MS(FIA):388.3 (M+H).

Example 13

[0310]

[0311]N-{4-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-phenyl}-2-phenoxy-acetamide:

[0312]¹H NMR (MeOD, 500 MHz): δ 8.34 (1H, d, J=5.5 Hz), 8.18 (2 H, d,J=9 Hz), 7.82 (2 H, d, J=7 Hz), 7.34-7.28 (4 H, m), 7.17 (1 H, t, J=8Hz), 7.09-6.99 (4 H, m), 6.56 (1 H, d, J=7 Hz), 4.69 (2 H, s) ppm.HPLC(purity, RT): >99% purity, 3.046 min. MS (FIA): 413.3 (M+H).

Example 14

[0313]

[0314]2-Phenoxy-N-{4-[2-(3-sulfamoyl-phenylamino)-pyrimidin-4-yl]-phenyl}-acetamide:

[0315]¹H NMR (TFA, 500 MHz): δ 9.87 (1H, s), 9.56 (1 H, d, J=7 Hz), 9.45(2 H, d, J=9 Hz), 9.10 (1 H, d, J=8 Hz), 9.03-9.00 (3 H, m), 8.91-8.85(3 H, m), 8.80 (1 H, d, J=7 Hz), 8.47-8.43 (3 H, m) 8.21-8.09 (4 h, m)5.90 (2 H, s) ppm. HPLC(purity, RT): >99% purity, 3.073 min. MS (FIA):476.3 (M+H).

Example 15

[0316]

[0317]N-{4-[2-(3-Amino-phenylamino)-pyrimidin-4-yl]-phenyl}-2-phenoxy-acetamide:

[0318]¹H NMR (MeOD, 500 MHz): δ 8.38 (1H, d, J=5.5 Hz), 8.14 (2 H, d,J=9 Hz), 7.96 (1 H, s), 7.78 (2 H, d, J=7 Hz), 7.33-7.22 (3 H, m),7.06-6.96 (5 H, m), 6.43 (1 H, m), 4.68 (2 H, s) ppm. HPLC(purity,RT): >99% purity, 2.811 min. MS (FIA): 412.3 (M+H)

[0319] Additional compounds of the invention are prepared using thegeneral methods described above and herein.

Example 16 JAK3 Inhibition Assay

[0320] Compound inhibition of JAK was assayed by the method described byG. R. Brown, et al, Bioorg. Med. Chem. Lett. 2000, vol. 10, pp 575-579in the following manner. Into Maxisorb plates, previously coated at 4°C. with Poly (Glu, Ala, Tyr) 6:3:1 then washed with phosphate bufferedsaline 0.05% and Tween (PBST), was added 2 μM ATP, 5 mM MgCl₂, and asolution of compound in DMSO. The reaction was started with JAK enzymeand the plates incubated for 60 minutes at 30° C. The plates were thenwashed with PBST, 100 μL HRP-Conjugated 4G10 antibody was added, and theplate incubated for 90 minutes at 30° C. The plate was again washed withPBST, 100 μL TMB solution is added, and the plates were incubated foranother 30 minutes at 30° C. Sulfuric acid (100 μL of 1M) was added tostop the reaction and the plate is read at 450 nm, and K_(i) values weredetermined.

[0321] Certain compounds of this invention have K_(i)s less than 5.0micromolar (μM) in the JAK3 inhibition assay. In certain otherembodiments, the following compounds have K_(i)s of 1.0 μM or less inthe JAK3 inhibition assay: IV-A(i)-1, IV-A(i)-2, IV-A(i)-4, IV-A(i)-5,IV-A(i)-6, IV-B(i)-1, IV-B(i)-2, IV-B(i)-3, IV-B(i)-4, IV-B(i)-5,IV-B(i)-6, IV-B(i)-7, IV-B(i)-8, IV-B(i)-9, IV-B(i)-10, IV-B(i)-11,IV-C(i)-15, and IV-D(i)-2.

Example 17 CDK2 Inhibition Assay

[0322] Compounds were screened for their ability to inhibit CDK-2/CyclinA using a standard coupled enzyme assay (Fox et al (1998) Protein Sci 7,2249). Reactions were carried out in 100 mM HEPES pH 7.5, 10 mM MgCl2,25 mM NaCl, 1 mM DTT and 1.5% DMSO. Final substrate concentrations inthe assay were 100 μM ATP (Sigma chemicals) and 100 μM peptide (AmericanPeptide, Sunnyvale, Calif.). Assays were carried out at 30° C. and 25 nMCDK-2/Cyclin A. Final concentrations of the components of the coupledenzyme system were 2.5 mM phosphoenolpyruvate, 350 μM NADH, 30 μg/mlpyruvate kinase and 10 μg/ml lactate dehydrogenase.

[0323] An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of CDK-2/Cyclin A, DTT and thetest compound of interest. 56 μl of the test reaction was placed in a384 well plate followed by addition of 1 μl of 2 mM DMSO stockcontaining the test compound (final compound concentration 30 μM). Theplate was preincubated for ˜10 minutes at 30° C. and the reactioninitiated by addition of 10 μl of enzyme (final concentration 25 nM).Rates of reaction were obtained using a BioRad Ultramark plate reader(Hercules, Calif.) over a 5 minute read time at 30° C. and K_(i) valueswere determined.

[0324] Certain compounds of this invention have K_(i)s less than 5.0micromolar (μM) in the CDK2 inhibition assay. In certain otherembodiments, the following compounds have K_(i)s of 1.0 μM or less inthe CDK2 inhibition assay: IV-B(i)-2, IV-B(i)-11, IV-C(i)-2, IV-C(i)-3,IV-C(i)-4, and IV-D(i)-4.

Example 18 JNK3 Inhibition Assays

[0325] Compounds were assayed for the inhibition of JNK3 by aspectrophotometric coupled-enzyme assay. In this assay, a fixedconcentration of activated JNK3 (10 nM) was incubated with variousconcentrations of a potential inhibitor dissolved in DMSO for 10 minutesat 30° C. in a buffer containing 0.1 M HEPES buffer, pH 7.5, containing10 mM MgCl₂, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvatekinase, 50 μg/mL lactate dehydrogenase, and 200 μM EGF receptor peptide.The EGF receptor is a phosphoryl acceptor in the JNK3-catalyzed kinasereaction. The reaction was initiated by the addition of 10 μM ATP andthe assay plate is inserted into the spectrophotometer's assay platecompartment that was maintained at 30° C. The decrease of absorbance at340 nm was monitored as a function of time. The rate data as a functionof inhibitor concentration was fitted to competitive inhibition kineticmodel to determine the K_(i).

[0326] Certain compounds of this invention have K_(i)s less than 5.0micromolar (μM) in the JNK3 inhibition assay. In certain otherembodiments, the following compounds have K_(i)s of 1.0 μM or less inthe JNK3 inhibition assay: IV-B(i)-2, and IV-B(i)-11.

Example 18 ZAP-70 Inhibition Assay

[0327] Compounds are screened for their ability to inhibit ZAP-70 usinga standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7,2249). Assays are carried out in a mixture of 100 mM HEPES 7.5, 10 mMMgCl₂, 25 mM NaCl, 2 mM DTT and 3% DMSO. Final substrate concentrationsin the assay were 100 μM ATP (Sigma Chemicals) and 20 μM peptide(poly-4EY, Sigma Chemicals). Assays are carried out at 30° C. and 60 nMZAP-70. Final concentrations of the components of the coupled enzymesystem were 2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg/ml pyruvatekinase and 10 μg/ml lactate dehydrogenase.

[0328] An assay stock buffer solution is prepared containing all of thereagents listed above, with the exception of ZAP-70 and the testcompound of interest. 55 μl of the stock solution is placed in a 96 wellplate followed by addition of 2 μl of DMSO stock containing serialdilutions of the test compound (typically starting from a finalconcentration of 15 μM). The plate is preincubated for 10 minutes at 30°C. and the reaction initiated by addition of 10 μl of enzyme (finalconcentration 60 nM). Initial reaction rates are determined with aMolecular Devices SpectraMax Plus plate reader over a 15 minute timecourse. K_(i) data are calculated from non-linear regression analysisusing the Prism software package (GraphPad Prism version 3.0a forMacintosh, GraphPad Software, San Diego Calif., USA).

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is Q-Ar¹,wherein Q is a C₁₋₂ alkylidene chain wherein one methylene unit of Q isoptionally replaced by O, NR, NRCO, NRCONR, NRCO₂, CO, CO₂, CONR,OC(O)NR, SO₂, SO₂NR, NRSO₂, NRSO₂NR, C(O)C(O), or C(O)CH₂C(O); Ar¹ is a5-7 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;wherein Ar¹ is optionally substituted with q independent occurrences ofZ—R^(Z); wherein q is 0-5, Z is a bond or is a C₁-C₆ alkylidene chainwherein up to two non-adjacent methylene units of Z are optionally andindependently replaced by CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO,NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR; andeach occurrence of R^(Z) is independently selected from R′, halogen,NO₂, CN, OR′, SR′, N(R′)₂, NR′COR′, NR′CON(R′)₂, NR′CO₂R′, COR′, CO₂R′,OCOR′, CON(R′)₂, OCON(R′)₂, SOR′, SO₂R′, SO₂N(R′)₂, NR′SO₂R′,NR′SO₂N(R′)₂, COCOR′, or COCH₂COR′; each occurrence of R isindependently hydrogen or an optionally substituted C₁₋₆ aliphaticgroup; and each occurrence of R′ is independently hydrogen or anoptionally substituted C₁₋₆ aliphatic group, a 3-8-membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-12 membered saturated, partially unsaturated, or fully unsaturatedbicyclic ring system having 0-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; or R and R′, two occurrences of R, or twooccurrences of R′, are taken together with the atom(s) to which they arebound to form an optionally substituted 3-12 membered saturated,partially unsaturated, or fully unsaturated monocyclic or bicyclic ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur; Z¹ is N or CH; Z⁷ is N or C(U)_(n)R^(Y); T and U are eachindependently a bond or a saturated or unsaturated C₁₋₆ alkylidenechain, wherein up to two methylene units of the chain are optionally andindependently replaced by CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO,NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR; m andn are each independently 0 or 1; R^(X) and R^(Y) are each independentlyselected from R or Ar¹; Z² is N or CR²; Z³ is N or CR³; Z⁴ is N or CR⁴;Z⁵ is N or CR⁵; and Z⁶ is N or CR⁶, wherein each occurrence of R², R³,R⁴, R⁵, or R⁶ is independently R^(U) or (V)_(p)R^(V), provided that a)no more than three of Z², Z³, Z⁴, Z⁵ or Z⁶ is N, and b) at least one ofZ³, Z⁴ or Z⁵ is CR³, CR⁴, or CR⁵, respectively, and at least one of R³,R⁴, or R⁵ is R^(U), each occurrence of R^(U) is NRCOR⁷, CONR(R⁷),SO₂NR(R⁷), NRSO₂R⁷, NRCONR(R⁷), NRSO₂NR(R⁷), or CONRNR(R⁷), wherein R⁷is (CH₂)_(t)—Y—R⁸, and t is 0, 1, or 2, Y is a bond or is O, S, NR⁹,—OCH₂—, —SCH₂, —NR⁹CH₂, O(CH₂)₂—, —S(CH₂)₂, or —NR⁹(CH₂)₂, and R⁸ isAr², or R⁸ and R⁹, taken together with the nitrogen atom, form anoptionally substituted 5-8 membered heterocyclyl or heteroaryl ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen orsulfur; each occurrence of V is a bond or a saturated or unsaturatedC₁₋₆ alkylidene chain, wherein up to two methylene units of the chainare optionally and independently replaced by CO, CO₂, COCO, CONR, OCONR,NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S,or NR; each occurrence of p is 0 or 1; each occurrence of R^(V) is R orAr²; and Ar² is a 5-7 membered saturated, partially unsaturated, orfully unsaturated monocyclic ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or an 8-12 memberedsaturated, partially unsaturated, or fully unsaturated bicyclic ringsystem having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; wherein Ar² is optionally substituted with rindependent occurrences of W-R^(W); wherein r is 0-3, W is a bond or isa C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene unitsof W are optionally replaced by CO, CO₂, COCO, CONR, OCONR, NRNR,NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, orNR; and each occurrence of R^(W) is independently selected from R′,halogen, NO₂, CN, OR′, SR′, N(R′)₂, NR′COR′, NR′CON(R′)₂, NR′CO₂R′,COR′, CO₂R′, OCOR′, CON(R′)₂, OCON(R′)₂, SOR′, SO₂R′, SO₂N(R′)₂,NR′SO₂R′, NR′SO₂N(R′)₂, COCOR′, or COCH₂COR′; provided that: a) when Z¹is N, Z⁷ is CH; and ring B is phenyl and at least one of R³ or R⁴ isNHCOR⁷, then R¹ is not phenyl only substituted with two or threeoccurrences of OR′; and b) when Z¹ is N, Z⁷ is CH; and ring B is phenyland at least one of R³ of R⁴ is NHCOR⁷, SO₂R⁷, CONRR⁷, then R¹ is notphenyl only substituted with one occurrence of —CON(R′)₂ in the paraposition.
 2. The compound according to claim 1, wherein Z¹ is N and thecompound has the structure II:


3. The compound of claim 1, wherein Z¹ is CH and amino pyridines ofgeneral formula III are provided:


4. The compound of claim 1, wherein R¹ is an optionally substitutedphenyl, cyclohexyl, cyclopentyl, pyridyl, morpholino, piperazinyl, orpiperidinyl group
 5. The compound of claim 1, wherein R¹ is anoptionally substituted from phenyl, cyclohexyl, or pyridyl group.
 6. Thecompound of claim 1, wherein R¹ is optionally substituted phenyl.
 7. Thecompound of claim 1, wherein q is 0, 1, 2, or 3 and each independentoccurrence of ZR^(Z) is C₁₋₄alkyl, N(R′)₂, OR′, SR′, CON(R′)₂, NR′COR′,NR′SO₂R′, or SO₂N(R′)₂.
 8. The compound of claim 1, wherein q is 1 andZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —S(O)₂NH₂.
 9. The compound of claim1, wherein q is 1, and ZR^(Z) is in the meta position and ZR^(Z) is—NH₂, —OH, C₁₋₄alkoxy, or —S(O)₂NH₂.
 10. The compound of claim 1,wherein (T)_(m)R^(X) and (U)_(n)R^(Y) are hydrogen, halogen, NO₂, CN,OR, SR or N(R)₂, or C₁₋₄aliphatic optionally substituted with oxo, OR,SR, N(R)₂, halogen, NO₂ or CN.
 11. The compound of claim 1, wherein(T)_(m)R^(X) and (U)_(n)R^(Y) are each independently hydrogen, Me, OH,OMe or N(R)₂.
 12. The compound of claim 1, wherein (T)_(m)R^(X) and(U)_(n)R^(Y) are each hydrogen.
 13. The compound of claim 1, whereinring B is one of rings i-xiv:


14. The compound of claim 1, wherein t is 0, Y is a bond, and R⁸ is anoptionally substituted aryl or heteroaryl moiety.
 15. The compound ofclaim 1, wherein t is 0, Y is a bond, and R⁸ is an optionallysubstituted heteroaryl moiety.
 16. The compound of claim 1, wherein R⁷is —CH₂—Y—R⁸, and Y is NR⁹, O or S, and R⁸ is an optionally substitutedaryl or heteroaryl moiety.
 17. The compound of claim 1, wherein R⁷ is—CH₂—Y—R⁸, and Y is NR⁹, O or S, and R⁸ is an optionally substitutedaryl moiety.
 18. The compound of claim 1, wherein t is 0 or 1, Y is NR⁹,and R⁸ and R⁹, taken together with the nitrogen atom, form a 5-8membered heterocyclyl or heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen or sulfur.
 19. The compoundof claim 1, wherein R⁸ is a 5- or 6-membered aryl or heteroaryl grouphaving one of the formulae:


20. The compound of claim 1, wherein R⁸ is a 5- or 6-membered heteroarylgroup having one of the formulae:


21. The compound of claim 1, wherein R⁸ and R⁹, taken together, form agroup having one of the formulae:


22. The compound of claim 1, wherein r is 0 or
 1. 23. The compound ofclaim 19, 20, or 21, wherein r is 1, 2, or 3, and each occurrence ofhalogen, C₁₋₄alkyl, —(R)₂, —OR, —SR, —SO₂N(R)₂, —N(R)SO₂R, —N(R)COR,—N(R)₂, —CH₂OR, —CH₂N(R)₂, or —CH₂SR.
 24. The compound of claim 19, 20,or 21, wherein t is 0, Y is a bond, and R⁸ is an optionally substitutedheteroaryl moiety selected from one of groups b through r.
 25. Thecompound of claim 24, wherein R⁸ is an optionally substituted heteroarylgroup b-i, k-i, or l-i.
 26. The compound of claim 1, wherein t is 1, Yis O, S or NR⁹, and R⁸ is optionally substituted phenyl.
 27. Thecompound of claim 1, wherein t is 0 or 1, Y is NR⁹, and R⁸ and R⁹, takentogether form an optionally substituted group selected from s, u or v.28. The compound of claim 1, wherein Z³ or Z⁵ is CR³ or CR⁵,respectively, and R³ or R⁵ is NRC(O)R⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸,wherein t is 0, 1 or 2, wherein Y is a bond or is O, S, NR⁹, —OCH₂—,—SCH₂, —NR⁹CH₂, O(CH₂)₂—, —S(CH₂)₂, or —NR⁹(CH₂)₂, and wherein R⁸ isAr², or R⁸ and R⁹, taken together with the nitrogen atom, form a 5-8membered heterocyclyl or heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen or sulfur, and compoundshave the formula II-A or III-A:


29. The compound of claim 28, wherein for compounds of formula II-A ringB is selected from i, ii, iii, iv, v, vii, viii, ix, x, xi, xii, or xiiiand compounds have one of formulas II-A-i, II-A-ii, II-A-iii, II-A-iv,II-A-v, II-A-vii, II-A-viii, II-A-ix, II-A-x, II-A-xi, II-A-xii, orII-A-xiii:


30. The compound of claim 28, wherein for compounds of formula III-Aring B is selected from one of i, ii, iii, iv, V, Vii, Viii, ix, x, xi,xii, or xiii and compounds have one of formulas III-A-i, III-A-ii,III-A-iii, III-A-iv, III-A-v, III-A-vii, III-A-viii, III-A-ix, III-A-x,III-A-xi, III-A-xii, or III-A-xiii:


31. The compound of claim 1, wherein Z⁴ is CR⁴, and R⁴ is NRC(O)R⁷,wherein R⁷ is (CH₂)_(t)—Y—R⁸, wherein t is 0, 1 or 2, wherein Y is abond or is O, S, NR⁹, —OCH₂—, —SCH₂, —NR⁹CH₂, O(CH₂)₂—, —S(CH₂)₂, or—NR⁹(CH₂)₂, and wherein R⁸ is Ar², or R⁸ and R⁹, taken together with thenitrogen atom, form a 5-8 membered heterocyclyl or heteroaryl ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen orsulfur, and compounds have one of formulas II-B or III-B:


32. The compound of claim 31, wherein for compounds of formula II-B,ring B is selected from i, ii, iii, iv, vi, viii, ix, xii, or xiv andcompounds have one of formulas II-B-i, II-B-ii, II-B-iii, II-B-iv,II-B-vi, II-B-viii, II-B-ix, II-B-xii, or II-B-xiv:


33. The compound of claim 31, wherein for compounds of formula III-B,ring B is selected from i, ii, iii, iv, vi, viii, ix, xii, or xiv andcompounds have one of formulas III-B-i, III-B-ii, III-B-iii, III-B-iv,III-B-vi, III-B-viii, III-B-ix, III-B-xii, or III-B-xiv:


34. The compound of claim 1, wherein Z³ or Z⁵ is CR³ or CR⁵,respectively, and R³ or R⁵ is C(O)N(R)(R⁷), wherein R⁷ is(CH₂)_(t)—Y—R⁸, wherein t is 0, 1 or 2, wherein Y is a bond or is O, S,NR⁹, —OCH₂—, —SCH₂, —NR⁹CH₂, O(CH₂)₂—, —S(CH₂)₂, or —NR⁹(CH₂)₂, andwherein R⁸ is Ar², or R⁸ and R⁹, taken together with the nitrogen atom,form a 5-8 membered heterocyclyl or heteroaryl ring having 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur andcompounds have one of formulas II-C or III-C:


35. The compound of claim 34, wherein for compounds of formula II-C,ring B is selected from i, ii, iii, iv, v, vii, viii, ix, x, xi, xii, orxiii and compounds have one of formulas II-C-i, II-C-ii, II-C-iii,II-C-iv, II-C-v, II-C-vii, II-C-viii, II-C-ix, II-C-x, II-C-xi,II-C-xii, or II-C-xiii:


36. The compound of claim 34, wherein for compounds of formula III-C,ring B is selected from i, ii, iii, iv, v, vii, viii, ix, x, xi, xii, orxiii and compounds have one of formulas III-C-i, III-C-ii, III-C-iii,III-C-iv, III-C-v, III-C-vii, III-C-viii, III-C-ix, III-C-x, III-C-xi,III-C-xii, or III-C-xiii are provided as depicted below:


37. The compound of claim 1, wherein Z⁴ is CR⁴, and R⁴ is C(O)N(R)(R⁷),wherein R⁷ is (CH₂)_(t)—Y—R⁸, wherein t is 0, 1 or 2, wherein Y is abond or is O, S, NR⁹, —OCH₂—, —SCH₂, —NR⁹CH₂, O(CH₂)₂—, —S(CH₂)₂, or—NR⁹(CH₂)₂, and wherein R⁸ is Ar², or R⁸ and R⁹, taken together with thenitrogen atom, form a 5-8 membered heterocyclyl or heteroaryl ringhaving 1-3 heteroatoms independently selected from nitrogen, oxygen orsulfur and compounds have one of formulas II-D or III-D:


38. The compound of claim 37, wherein for compounds of formula II-D,ring B is selected from i, ii, iii, iv, vi, viii, ix, xii, or xiv andcompounds have one of formulas II-D-i, II-D-ii, II-D-iii, II-D-iv,II-D-vi, II-D-viii, II-D-ix, II-D-xii, or II-D-xiv:


39. The compound of claim 37, wherein for compounds of formula III-D,ring B is selected from i, ii, iii, iv, vi, viii, ix, xii, or xiv andcompounds have one of formulas III-D-i, III-D-ii, III-D-iii, III-D-iv,III-D-vi, III-D-viii, III-D-ix, III-D-xii, or III-D-xiv:


40. The compound of claim 1, where R¹ is optionally substituted phenyland ring B is an optionally substituted phenyl group and compounds havethe general formulas IV or V:


41. The compound of claim 40, wherein, R³ is NRCOR⁷ and compounds havethe general formulae IV-A-(i) or V-A-(i):


42. The compound of claim 40, wherein R⁴ is NRCOR⁷ and compounds havethe general formulae IV-B-(i) or V-B-(i):


43. The compound of claim 40, wherein R³ is CONRR⁷ and compounds havethe general formulae IV-C-(i) or V-C-(i):


44. The compound of claim 40, wherein R⁴ is CONRR⁷ and compounds havethe general formulae IV-D-(i) or VII-D-(i):


45. The compound of claim 40, wherein R¹ is optionally substitutedphenyl, ring A is pyrimidinyl or pyridyl, ring B is phenyl, and R², R⁵,and R⁶ are each hydrogen, and compounds have the general formulae VI andVII:


46. The compound of claim 40 or 45, wherein a. q is 0 or 1 and ZR^(Z) is—NH₂, —OH, C₁₋₄alkoxy, or —SO₂NH₂; b. R³ is NRCOR⁷, wherein R⁷ is(CH₂)_(t)—Y—R⁸, and t is 0, Y is a bond, and R⁸ is phenyl (a), or is anoptionally substituted heteroaryl moiety selected from one of groups bthrough r, and wherein r is 0 or 1, and WR^(W) substituents are halogen,C₁₋₄alkyl, —(R)₂, —OR, —SR, —SO₂N(R)₂, —N(R)SO₂R, —N(R)COR, —N(R)₂,—CH₂OR, —CH₂N(R)₂, or —CH₂SR; and c. R⁴ is hydrogen.
 47. The compound ofclaim 40 or 45, wherein: a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH,C₁₋₄alkoxy, or —SO₂NH₂; b. R³ is CONRR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸,and t is 0, Y is a bond, and R⁸ is phenyl (a) or is an optionallysubstituted heteroaryl moiety selected from one of groups b through r,and wherein r is 0 or 1, and WR^(W) substituents are halogen, C₁₋₄alkyl,—(R)₂, —OR, —SR, —SO₂N(R)₂, N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR,—CH₂N(R)₂, or —CH₂SR; and c. R⁴ is hydrogen.
 48. The compound of claim40 or 45, wherein: a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy,or —S(O)₂NH₂; b. R⁴ is NRCOR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 0,Y is a bond, and R⁸ is phenyl (a) or an optionally substitutedheteroaryl moiety selected from one of groups b through z, and wherein ris 0 or 1, and WR^(W) substituents are halogen, C₁₋₄alkyl, —(R)₂, —OR,—SR, 13 SO₂N(R)₂, —N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR, —CH₂N(R)₂, or—CH₂SR; and c. R³ is hydrogen.
 49. The compound of claim 40 or 45,wherein: a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or—S(O)₂NH₂; b. R⁴ is CONRR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 0, Yis a bond, and R⁸ is phenyl (a) or an optionally substituted heteroarylmoiety selected from one of groups b through z, and wherein r is 0 or 1,and WR^(W) substituents are halogen, C₁₋₄alkyl, —(R)₂, —OR, —SR,—SO₂N(R)₂, —N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR, —CH₂N(R)₂, or —CH₂SR;and c. R³ is hydrogen.
 50. The compound of claim 40 or 45, wherein: a. qis 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —S(O)₂NH₂; b. R³ isNRCOR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 0 or 1, Y is NR⁹, and R⁸and R⁹, taken together with the nitrogen atom, form a group selectedfrom s, t, u, or v, and wherein r is 0 or 1, and WR^(W) substituents arehalogen, C₁₋₄alkyl, —(R)₂, —OR, —SR, —SO₂N(R)₂, —N(R)SO₂R, —N(R)COR,—N(R)₂, —CH₂OR, —CH₂N(R)₂, or —CH₂SR; and c. R⁴ is hydrogen.
 51. Thecompound of claim 40 or 45, wherein: a. q is 0 or 1 and ZR^(Z) is —NH₂,—OH, C₁₋₄alkoxy, or —S(O)₂NH₂; b. R³ is CONRR⁷, wherein R⁷ is(CH₂)_(t)—Y—R⁸, and t is 0 or 1, Y is NR⁹, and R⁸ and R⁹, taken togetherwith the nitrogen atom, form a group selected from s, t, u, or v, andwherein r is 0 or 1, and WR^(W) substituents are halogen, C₁₋₄alkyl,—(R)₂, —OR, —SR, —SO₂N(R)₂, —N(R)SO₂R, —N(R)COR, —N(R)₂, —CH₂OR,—CH₂N(R)₂, or —CH₂SR; and c. R⁴ is hydrogen.
 52. The compound of claim40 or 45, wherein: a. q is 0 or 1 and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy,or —S(O)₂NH₂; b. R⁴ is NRCOR⁷, wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 0or 1, Y is NR⁹, and R⁸ and R⁹, taken together with the nitrogen atom,form a group selected from s, t, u, or v, and wherein r is 0 or 1, andWR^(W) substituents include halogen, C₁₋₄alkyl, NH₂, OH, SH, SO₂NH₂,C₁₋₄alkoxy, C₁₋₄thioalkyl, CH₂OR, CH₂N(R)₂, or CH₂SR; and c. R³ ishydrogen.
 53. The compound of claim 40 or 45, wherein: a. q is 0 or 1and ZR^(Z) is —NH₂, —OH, C₁₋₄alkoxy, or —S(O)₂NH₂; b. R⁴ is CONRR⁷,wherein R⁷ is (CH₂)_(t)—Y—R⁸, and t is 0 or 1, Y is NR⁹, and R⁸ and R⁹,taken together with the nitrogen atom, form a group selected from s, t,u, or v, and wherein r is 0 or 1, and WR^(W) substituents are halogen,C₁₋₄alkyl, —(R)₂, —OR, —SR, —SO₂N(R)₂, —N(R)SO₂R, —N(R)COR, —N(R)₂,—CH₂OR, —CH₂N(R)₂, or —CH₂SR; and c. R³ is hydrogen.
 54. The compound ofclaim 1, having one of the following structures:


55. A pharmaceutical composition comprising a compound according toclaim 1, and a pharmaceutically acceptable carrier, adjuvant, orvehicle.
 56. The composition of claim 55, further comprising anadditional therapeutic agent selected from a chemotherapeutic oranti-proliferative agent, a treatment for Alzheimer's Disease, atreatment for Parkinson's Disease, an agent for treating MultipleSclerosis (MS), a treatment for asthma, an agent for treatingschizophrenia, an anti-inflammatory agent, an immunomodulatory orimmunosuppressive agent, a neurotrophic factor, an agent for treatingcardiovascular disease, an agent for treating destructive bonedisorders, an agent for treating liver disease, an agent for treating ablood disorder, or an agent for treating an immunodeficiency disorder.57. A method of inhibiting JAK kinase activity in a biological sample ora patient, comprising the step of contacting said biological sample orpatient with: a) the composition of claim 55; or b) the compound ofclaim
 1. 58. A method of treating or lessening the severity of a diseaseor disorder selected from an immune response, an autoimmune disease, aneurodegenerative disorder, or a solid or hematologic malignancycomprising administering to a patient in need thereof a compound ofclaim 1 or a composition of claim
 55. 59. The method of claim 58,wherein the disease is an allergic or type I hypersensitivity reaction,asthma, transplant rejection, graft versus host disease, rheumatoidarthritis, amyotrophic lateral sclerosis, multiple sclerosis, Familialamyotrophic lateral sclerosis (FALS), leukemia, or lymphoma.